Good morning and welcome to the Lexeo Therapeutics Webcast P resentation of Interim Phase I-II Clinical Data of LX1001 for the t reatment of APOE-Associated Alzheimer's Disease. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will hold a question-and-answer session. To ask a question at a time, please press star followed by one on your touch-tone phone. If anyone has difficulty hearing the conference call, please press star zero for operator assistance. As a reminder, this call is being recorded today, Wednesday, October 16, 2024. I would now like to turn the conference call over to Rand Monaghan, Vice President, Finance of Lexeo Therapeutics. Rand, please go ahead. This morning, we issued a press release outlining the interim clinical data, which is available on our website at lexeotx.com and filed an 8-K with the SEC. Joining us on today's call will be Nolan Townsend, Chief Executive Officer, and Dr. Sandi See Tai, Chief Development Officer. Also available for questions is Dr. Sam Gandy, Mount Sinai Professor of Alzheimer's Disease Research and Chairman Emeritus of the National Medical and Scientific Advisory Council of the Alzheimer's Association. Before we begin, I would like to remind you that this call will contain forward-looking statements for the purposes of the Safe Harbor Provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these as a result of various important factors, including those discussed in our filings with the SEC. With that, I will turn the call over to Nolan. Thank you, Rand, and thank you, everyone, for joining us. Earlier today at the Clinical Trials on Alzheimer's Disease Conference, we were pleased to release interim data from the phase II clinical trial of LX1001 for the treatment of APOE4-associated Alzheimer's disease. LX1001 is a unique genetic approach to treating this high-risk category of Alzheimer's patients. And the interim data we will discuss today show a highly encouraging and consistent pattern of reduction across CSF tau biomarkers and tau PET imaging, alongside APOE2 protein expression in all participants. Furthermore, we observed a favorable safety profile with no reports of ARIA. Before we dive into the data today, I'd like to quickly remind everyone of our broader genetic medicines pipeline. LX1001 is the most advanced program in our pipeline of candidates targeting APOE4-associated Alzheimer's disease, and the phase II study completed dosing late last year. We also have two preclinical programs in this therapeutic area: LX1021, which incorporates the potent Christchurch mutation into the APOE2 transgene, and LX1020, which utilizes microRNA to suppress APOE4. We also have a pipeline in cardiovascular genetic medicine, including two clinical stage programs, one in Friedreich's ataxia cardiomyopathy and the other in PKP2 arrhythmogenic cardiomyopathy. Importantly, we retain global rights to all programs in our pipeline. I'd like to now share more background on APOE4 homozygotes, or those with two copies of the APOE4 allele. We estimate that there are approximately 900,000 APOE4 homozygotes with Alzheimer's in the U.S., and this population has the highest genetic risk factor for developing Alzheimer's disease, approximately 15 times greater than the general population. Nearly all APOE4 homozygotes will develop the disease in their lifetime, with earlier symptom onset and faster rate of cognitive decline than other APOE genotypes. Importantly, E4 homozygotes also have limited treatment options, as the currently approved amyloid-targeted therapies carry an increased risk of amyloid-related imaging abnormalities known as ARIA, which includes brain swelling and microhemorrhages, and the risk of these adverse events are the highest in the E4/E4 population. For this reason, these therapies carry box warnings recommending genetic testing to check the E4 allele before prescribing, as well as MRI monitoring of E4/E4 patients should a physician choose to initiate therapy. Moreover, the anti-amyloid therapies also demonstrate a lower efficacy on cognitive measures in the E4 homozygous group. Given these safety risks and lower efficacy for E4/E4 patients, we believe that there continues to be higher unmet need for these patients. To understand what is happening at the biological level, we first have to understand the role of APOE4, which is a driver of Alzheimer's disease and can independently impact amyloid pathology, tau pathology, neurotoxicity, neuroinflammation, and eventual synaptic and neuronal dysfunction. These underlying genetics are not currently addressed by existing therapies or any antibody mechanism of action and are the thesis for our approach that acts upstream of any particular pathway, potentially modifying pathology at multiple levels. In contrast to these toxic pathways, the APOE2 isoform has been shown to independently drive many neuroprotective pathways. This is most evident by the fact that 2/4 heterozygotes have lower risk of Alzheimer's onset and slower disease progression, and 2 homozygotes have significantly reduced risk of Alzheimer's disease compared to other genotypes. In terms of amyloid biology, the buildup of A beta plaque can begin years or even decades before the onset of Alzheimer's symptoms. Though expression of APOE2 may not clear pre-existing amyloid plaque, there's evidence suggesting that it can suppress A beta toxicity and therefore indirectly impact tau, a well-known driver of pathology in this disease. Independent of amyloid, there is also increasing evidence that APOE2 directly modulates tau toxicity by regulating tau phosphorylation, accumulation, and inflammation. Tau pathology occurs later in the course of disease and, as we've come to understand in recent years, may be more closely correlated with cognitive decline in Alzheimer's disease, so if we can impact tau, we believe we are likely to address cognitive decline as well. Ultimately, the hypothesis we are exploring is that the delivery of APOE2 will increase the ratio of 2/4 in a 4 brain, which will simultaneously dilute the effects of APOE4 toxicity while adding the protective benefits of APOE2. Similar to other recessive genetic diseases, we believe that a small amount of normal protein can provide meaningful clinical benefit. This is why we believe delivery of LX1001 could act upstream of any particular pathway or target, potentially mediating both efficacy and tolerability. Here you can see that hypothesis in the LX1001 mechanism of action. We're utilizing the AAVrh10 vector administered via intrathecal or intracisternal injection into the central nervous system to deliver the protective APOE2 allele to APOE4 homozygotes. To our knowledge, this is the first and only clinical stage gene therapy program targeting the underlying genetic cause of APOE4-associated Alzheimer's disease with a clinically validated capsid with a favorable safety profile and a differentiated single administration therapy. In this initial LX1001 phase II study, we had several primary goals. We first wanted to demonstrate APOE2 expression in the CSF, observe signals of downstream biologic activity, and demonstrate that LX1001 administration was well tolerated, which is especially important in this population that has been associated with higher ARIA rates. Overall, we are pleased with the results we have observed, and we believe that our objectives have been achieved and that this results clearly support further evaluation. I will now turn it over to Dr. Sandi See Tai to review the interim data. Thank you, Nolan. On this slide, you can find the key details of the phase II study design. It's a 52-week open-label trial that enrolled 15 APOE4 homozygotes with mild cognitive impairment, mild dementia, or moderate dementia due to Alzheimer's across four ascending dose cohorts. Enrollment was completed in the fourth quarter of last year, and today we will be sharing 12-month safety and biomarker data from cohorts one, two, and three, and six-month data from cohort four. I will note that although 15 patients were dosed with LX1001, two patients did not complete the protocol-required visits or testing at six and 12 months. So we have noted the n for each analysis on the following slide. Here you see the baseline characteristics for all 15 patients dosed in the study. Importantly, you can see that the patients with moderate dementia were clustered in dose cohorts one and three, whereas cohort two primarily included patients with mild cognitive impairment. So keep that in mind as we review the data, as you will see a general pattern of greater treatment effect in these moderate dementia patients. These patients overall also demonstrated high amyloid and tau burden at baseline. Moving on to safety, LX1001 was well tolerated across all four dose cohorts, and importantly, there were no reports of ARIA, which was an elevated risk for APOE4 homozygotes in the amyloid-targeting therapy studies, as Nolan discussed earlier. Transient CSF pleocytosis was observed, but it was not correlated with dose levels and most resolved by 12 months with no significant adverse events associated with the pleocytosis. Four serious adverse events were reported in the study. Three were assessed as unrelated to treatment, and one event of mild to moderate sensorineural hearing loss was assessed as possibly related to treatment. I can share that this patient's hearing is reportedly improving, and repeat audiometry is pending. Finally, cognitive testing was performed primarily for safety in this study. No safety signal was observed across the ADAS-Cog13, CDR-SB, or MMSE scales. No clear pattern of change was observed across these scales, which was not surprising given that larger sample sizes are needed to assess Alzheimer's progression given the wide interindividual variability. You can see the main change from baseline at 12 months in the LX1001 study across the measures below, and on average, these rates of progression are generally in line with what you would expect to see based on reported data in patients with early Alzheimer's and high tau burden. We hope in the next study to further evaluate these measures with a larger trial size. Now looking at APOE2 protein expression, it's important to note that our goal in this study was to look for expression with increases in a dose-dependent manner and then observe the impact on downstream markers associated with Alzheimer's pathology. We did not have a predefined target level of expression in mind, and ultimately, we did achieve our objective of seeing expression alongside corresponding improvement on biomarkers, which we will show you later in the presentation. On this slide, you can see APOE2 protein expression in the CSF, which was increased in all participants with a dose-dependent increase and durability out to 12 months. This demonstrates that we are achieving both transduction and expression of APOE2 in the brain as expected. In the middle chart, you can see that APOE4 expression is largely stable between baseline and month 12. Looking at the ratio of APOE2 expression relative to the existing APOE4, we again see a consistent pattern of dose and time-dependent increase in expression with continuing durability at month 12. We did have one patient in cohort three that showed the highest expression, which we have called out on the slide and not included in the mean, as we do not have 12-month data from this patient. Of note, you will see on the following slides that these protein levels appear to be associated with improvement in key clinical biomarkers, which we will review. Looking first at amyloid, let me orient everyone to this slide. Each bar represents an individual patient in the study and their change versus baseline. All bars are at last follow-up with most at 12 months except cohort four, where we are still awaiting the 12-month data, and one patient in cohort three sat at outlier with the highest expression who unfortunately did not consent to the lumbar puncture at 12 months. Looking first at Aβ42/40 ratio, LX1001 appears to stabilize Aβ42/40 in the CSF, as most patients are staying relatively close to baseline. This result aligns with our understanding of APOE2 and its role in the normalization of soluble Aβ. In amyloid PET on the right, we see again the majority of patients, eight of 11, have minimal change from baseline. Again, amyloid progression appears to be relatively stabilized. This next slide further cements our excitement on the data. In these two charts, we see a consistent reduction in CSF p-tau and p-tau181 in the majority of patients, nine of 13, and across all dose cohorts. These data demonstrate that the APOE2 protein being expressed by LX1001 is having the desired impact on downstream biology linked to disease progression. In an effort to put these reductions into context and with limited longitudinal data on the natural history of progression in APOE4 homozygotes, we have included some references to certain mean data reported from the Lecanemab phase 3 study on the CSF tau biomarker measures, which can be seen as the dotted blue line on the chart. Of course, these are different studies with different designs, inclusion criteria, and patient baselines. In particular, we would point out that the mean data shown from the Lecanemab trial includes all APOE genotypes and does not include any patients with moderate dementia at baseline. The top dotted line reflects the reported change from baseline in the placebo arm of the Lecanemab phase 3 study, which we believe highlights the natural trend of increasing tau pathology in Alzheimer's disease. Now, when looking at LX1001, we are seeing a reduction or an improvement in over two-thirds of our patients from baseline. We are also seeing the most significant treatment effect in patients with moderate dementia, the light blue bars, which is notable as it demonstrates our potential to treat a population with more severe disease that is typically excluded from clinical research. On this slide, we want to share additional measures of CSF p-tau that we believe confirm the pattern of improvement shown on the previous slide. These measures were added to the study, and today we only have data to share for cohorts two and three, as results from cohort four are not yet available, but again, you can see improvement in the majority of patients relative to baseline. For CSF p-tau217, you can also see improvement in five of six patients relative to natural history data in Alzheimer's disease, although this is not specific to APOE4 homozygotes, which may demonstrate even faster progression without treatment. Overall, the consistent pattern of improvement we are seeing here across all CSF tau biomarkers and across the majority of participants gives us confidence in the potential of LX1001 to have a reliable and consistent biological impact on tau pathology. This is critical because accumulation of tau is correlated with cognitive decline in Alzheimer's disease, and we believe that if we can impact tau, we may be able to impact cognitive and functional decline over time as well. In Tau PET, we are also seeing consistent reduction, which is encouraging because, of course, these results measure tau burden in the brain and not just the CSF. Tau PET analysis was added to the study after cohort two, so we are only able to share results from cohorts three and four today, with 12-month data for cohort four still pending. On the left, you can see that its six-month tau burden is reduced globally from baseline in five of six patients, and we have also highlighted the outsized reduction in the cohort three participant with the highest APOE2 expression. On the right, you can see the 12-month imaging from another patient in cohort three. tau is represented in red on the images, and you can see this participant showed noticeable improvement in tau burden at 12 months when compared to baseline. On this slide, we are showing reductions in tau PET across all regions of interest. The majority of patients, four out of six in the sample, experienced reductions in tau burden in all six brain regions, and we look forward to understanding the pattern observed at 12 months once we have additional data from cohort four. So, to summarize our findings, LX1001 has been well tolerated across all dose cohorts with no reported events of ARIA. We have achieved APOE2 expression in the CSF of all participants with a dose and time-dependent increase in 2 to 4 expression, with stabilization of amyloid pathology and a consistent reduction in key tau biomarkers. Together, these data give us confidence on the ability to utilize gene therapy, delivering APOE2 to treat APOE4 associated Alzheimer's disease and support continued development. Finally, to close this section, we point out some of the themes we've observed over the last several years as it relates to our regulatory strategy for this program. The first is the heightened collaborative environment in Alzheimer's and in gene therapy from CBER, which highlights the potential for accelerated approval based on surrogate endpoints and for which there is regulatory precedent using amyloid PET. The second tenet of the strategy is confidence in exploring tau PET as a surrogate endpoint for Alzheimer's disease. Studies have shown that tau pathology is closely correlated with cognitive outcomes in Alzheimer's disease, potentially more closely correlated than amyloid, and we believe this may be an appropriate surrogate endpoint for future studies. We have initiated FDA engagement to discuss the next phase of development, so we expect to provide an update on regulatory progress in 2025. With that, I will now turn it back over to Nolan to close out today's call. Thank you, Sandi. Like you, I'm very encouraged by the interim data shared today and the potential for LX1001 to deliver a targeted approach to treating APOE4 associated Alzheimer's disease. As we've shown today, we believe this unique mechanism has the potential to act upstream of Alzheimer's biology and impact multiple pathways associated with the disease. We believe the biomarker data presented today validates this unique and exciting approach for APOE4 homozygous patients for whom the limited treatment options available today may not be suitable. In terms of next steps, we have initiated engagement with the FDA, which will determine the next development steps for the program, including the possibility for accelerated approval. In addition, ongoing business development discussions are underway. We expect to provide an update on regulatory interactions and further LX1001 plans in 2025. Thank you for your time this morning. We will now take questions. As mentioned at the top of the call, we are joined by Dr. Sam Gandy as well for the Q&A. At this time, I would like to remind everyone, in order to ask a question, press star one on your telephone keypad. We will pause for just a moment to compile the Q&A roster. Your first question comes from the line of Tess Romero with J.P. Morgan. Your line is open. Great. Good morning, Nolan and team. Thanks so much for taking our question here. A couple from us. First, on the reported safety, what makes you believe the event of mild, moderate, sensorineural hearing loss is possibly related to treatment? And can you provide a little bit more additional color on the timing of this event? And as you think about what the etiology could be here, how do you and your investigators think about this? And we just wanted to clarify, were there any other treatment-related AEs? And then we had one follow-up. Okay. Thanks, Tess, for the question. I think I'll ask Sandi to comment on the hearing loss adverse event and the other SAEs. Yeah. So thanks for the question. So just to answer that question, this event occurred approximately three months after dosing. I think what led to us saying that it may be possibly related is that it was a relatively acute onset, though I think that we have ruled out other causes, so it's not clear this particular patient has a family history of hearing loss. What we do know in follow-up is that this patient, excuse me, appears to have some improvement in their hearing loss, and so a repeat hearing testing is pending. In terms of the etiology, we've tried to explore the literature as well as spoken with several experts in the area. We've also reviewed the event with our data safety monitoring board, and at this stage, do not feel that it required any changes to our ongoing protocol. We certainly continue to monitor the safety in the study, and in particular, with the follow-up for this patient. In terms of other treatment-related AEs, we have not seen any pattern or reports in that regard. Oka y. Great. Very helpful. Thank you. And as you think about the path forward here, bridging off this data, aside from moderate dementia patients observing, it looks like a more pronounced response to treatment. Are there any other characteristics of patients that could be a predictor of response? Thanks so much. Thanks, Tess. Maybe I'll take that one. I think what we were excited about in this data set was that we were seeing an impact on tau biomarkers that is roughly equivalent to some of the commercially approved therapies. But we are seeing this without safety events of ARIA, which is obviously very pronounced in some of the commercially approved therapies. We're seeing this with the APOE4 population, which today, the benefit-risk profile in being treated with some of the commercially approved therapies may not make sense for that group. So I think today, in terms of exploration, obviously, tau becomes a very important theme for the path forward and as a surrogate endpoint. And obviously, the more pronounced treatment effect in moderates is something that is notable. I would also note that moderates have not been well studied in some of the other therapies, and so that is a possibility for a population of very high immunity as well. So I would just say, with that summary, that's the direction of travel and more to come on earlier populations. But I think we can see here that probably the treatment effect across the moderates is one that needs to be further explored. Great. Thank you. Our next question comes from the line of Paul Matteis with Stifel. Your line is open. Hey, this is James on for Paul. Thanks so much for taking our questions. Just two quick ones from us. One, I guess, based on these data, how are you thinking about kind of picking a go-forward dose and what is the right dose to kind of carry forward? And two, I guess, just what level or have you had any sort of indication from regulators yet around the potential of tau as a surrogate? Thanks so much. Yep. So thanks for the question. I think one of the elements of this study is that we enroll patients across the range of the disease. So as you've seen, cohorts one and three primarily consist of moderate patients. Cohorts two and four primarily consist of mild MCI patients. I think in terms of observing the treatment effect in biomarkers like tau, you cannot necessarily look at them across cohorts on a like-to-like basis. I think we're seeing great trends in tau. We're certainly seeing those more substantially in the moderate patients. But I think to compare them across those cohorts because of the different starting baselines is a challenge. But where we do have, let's say, equal starting points is with respect to APOE2 expression. All the patients obviously start with zero APOE2 at baseline, and then we see these dose-dependent increases in APOE2 across the cohorts. As we are observing, to some degree, a dose response, and the best example of that is the cohort three patient who had the high APOE2 response and that corresponded to greater reductions in tau PET. We do believe there is a dose response associated with the therapy. So given that, the endpoints we would likely consider for a pivotal study would be something in the direction of Tau PET potentially combined with ApoE expression. I would indicate that ApoE expression levels and achieving the highest ApoE expression levels would be the focus of a going forward dose. So in that vein, I would suggest that probably the cohort four dose would be the right one to take forward. But I think this would be a function of conversations with the FDA about that strategy and those endpoints. It's early to comment on the FDA's position on the surrogate endpoints. Those discussions are ongoing. We will be able to give an update on that in 2025 with respect to those endpoints. But I would note, I think the precedent exists to support such a strategy. As you're aware, Lecanemab was accelerated approval on amyloid PET, and there's increasing evidence that tau is more closely correlated to cognitive decline. So it would follow that tau PET would be a potentially compelling surrogate endpoint to indicate this link to cognitive decline. So more to come on that. We're in ongoing discussions with the FDA, and we will be able to provide an update on the regulatory path forward in addition to the path forward from a business development perspective as well in 2025. Awesome. Thanks so much. Your next question comes from the line of Brian Skorney with Baird. Your line is open. Mr. Skorney, please check if your line is on mute. You have an open line now. Thank you very much. Good morning, everyone. Thanks for taking the question. Congrats on the data. I guess my first question was, is there a difference in terms of baseline tau levels across different groups? Like did the moderate dementia patients have a substantially higher baseline tau measurement than the MCI or mild patients? And just wondering if you calculated an R-squared for the correlation between the APOE2 expression and any of the tau measurements. Thanks. Thanks, Brian. I mean, the moderate patients did have higher starting tau burden. So that is an attribute of the disease that as the disease progresses, you typically see greater accumulation of tau tangles, and that would certainly represent it within the moderate population. In terms of a direct correlation, we did not conduct an analysis of that profile. Obviously, with the small sample set and a 15-patient phase 1 study, drawing such statistical correlations is a challenge. But I think we do see very clear trends in tau within the population, and we see even more substantial trends in that moderate group. But we did not conduct the statistical analysis against that from II relative to tau. Great. Thanks. And your next question comes from the line of Mani Foroohar with Leerink. Your line is open. Thanks for taking the question. I guess a quick one for the Gandy, not the [uncertain]. How would you interpret the numerically, the APOE2/APOE4 ratio that we're seeing on slide 11 of the slide deck that Nolan and team were kind enough to share? And separately, how should we think about the distribution across areas of the brain in terms of thinking about frontal lobe versus other areas, entorhinal cortex, etc., as seen on slide 16? How should we interpret that? At what point is there an adequate pool of data in terms of number of patients, duration of follow-up for that to be something meaningful? Yeah. Thanks for the question. I think with the 2/4 ratio, you would ideally like to get as close to one-to-one as possible. So since the safety signal shows that this is very safe, and you have a long way to go before you would get to that, I think that you have plenty of room to go in terms of increasing the dose to try and get toward that. I mean, the idea with humans is that 2/2 is so protective that 2/2 are roughly the same as 4/4 in terms of risk. So that's the sort of theoretical goal. The importance of the Tau PET is to look at the regions of the brain that you know are involved in cognition and speech and to try and correlate symptoms with those changes, and you can do that much better with Tau PET than with a biofluid biomarker, which sort of averages all the brain regions into the CSF or the blood. Great. I guess as a broader follow-up, looking over at slide 11, obviously, we have different levels of follow-up from the different cohorts. This is for the Lexeo team as well as for you, Dr. Gandy. How should we think about cohort four going forward, given what we've seen from cohorts one, two, three so far, to expect improvement in a two-to-four ratio between month six to month twelve? Or is that too hard to call for at this point? Yeah. So, maybe I'll provide some additional comments on the two-to-four ratio. So while I agree genetically, heterozygotes potentially have this one-to-one or even potentially lower than that ratio, we did not go into this study with the predefined level of APOE2 that we were seeking to achieve. What we wanted to look at was the correlation of levels of 2 that we did achieve to some of the downstream Alzheimer's biomarkers. And I think that that's the most important aspect in regards to treating this disease. I mean, what matters here is what will impact cognition. And we think tau is the best indicator of a biomarker that will actually predict the impact on cognition. So irrespective of the level of 2 expression, the fact that we are seeing these improvements in tau biomarkers, from our point of view, is a positive signal. In respect to the difference from month six and month 12, I wouldn't expect to see any dramatic shifts in the E2 expression. I would expect it to look a lot like month six as we saw in the other cohorts. But I would note that we did see, for example, in the patients that had higher expressing E2, we saw greater impact on tau on average, including this cohort three outlier. So I think that that's the focus for us going forward is how does E2 impact tau, and then tau obviously as a potential surrogate endpoint for the future study. That's helpful. That's helpful. Your next question comes from the line of Geulah Livshits with Chardan. Your line is open. Good morning, and thanks for taking the question. You talked about the greater treatment effect that you're seeing in patients with moderate disease that might have the higher tau burden at baseline. Can you elaborate a little bit on how we should think about why that might be happening and kind of what gives you confidence that that might continue to extend in, let's say, a larger study? Thanks. Maybe that's a question that I'll ask Sandi to answer, and then maybe Dr. Sandi, I'll ask him to add some comments to it as well. Yeah. If we think about sort of the sequence and progression and the pathology associated with Alzheimer's, often the pathway in terms of laying down A beta is probably happening for many years, if not decades, prior to onset of symptoms, and so immune health sort of builds on that And that's where, as we look at the more moderate patients, those neurofibrillary tangles are ones where you still have the ability to still impact. And therefore, I think for these more advanced patients, it's where, while they're still demonstrating tau progression, that we have the ability to actually show the impact of the therapeutic in that area. So I think that that's what makes sense for us in terms of thinking of the timeline when we intervene for these patients and the ability to demonstrate the treatment effect. And Dr. Gandy, if you have any additional comments there as well? Yeah. I think the key relevant science here has evolved rather recently, and that is the association between APOE4 and inflammation and tauopathy and amyloid-independent pathways. We used to always think that the toxicity or that Alzheimer's disease evolved from amyloidosis that was driving tauopathy. We now have clear evidence that there's direct communication, there's direct activation of inflammatory pathways and of tauopathy pathways that do not require amyloid. In fact, there are even examples of genes that make people better clinically and make their tauopathy disappear, but even make their amyloid worse. But I think this is all, though it's newer science, I think this is a very exciting result. Great. Thanks. Your next question comes from the line of Luca Issi with RBC Capital Markets. Your line is open. Oh, great. Thanks so much for taking my question and congrats on the data. Maybe two quick ones here. The first is, I think you're making an argument that the greatest effect is seen in the moderate patients, at least from a biomarker standpoint. But what about function? Again, I appreciate the data super early and the n is small, but how does the functional data look like when you slice it between moderate versus mild? Do you see any signals in the moderate patients in CDR-SB or ADAS-Cog or MMSE? Again, any color there would be much appreciated. And then maybe on tau, I think you're showing data for both total as well as phosphorylated tau as well as p-tau 181, 217, 231. Can you just maybe talk about the significance of each of these measurements and which one you think is most important? Thanks so much. Okay. Thanks, Luca. So maybe I'll address the first question at the outset. So this study was not powered to show a benefit in cognitive decline. At 15 patients, dose ranging without a control group, there would be no ability to draw any conclusion on cognitive decline. As you're aware, for example, the Lecanemab pivotal study, I believe, was over 1,500 patients in order to demonstrate that effect. So that was not a goal of the study, and I think to try to draw any conclusion in the absence of a control group, in the absence of powering to show that benefit would be a challenge here. We did include cognitive decline measures from a safety perspective. I'd say some of them have improved, some of them have worsened slightly. It's not clear whether those are better or worse than natural history for a similar set of patients for the reasons that I said, so I just would say, from a cognitive perspective, that this was not a goal of a 15-patient study, that we don't have any conclusions to draw there. However, one point I would note is I think all of the existing Alzheimer's therapies, when you look at the data from the existing programs, have shown that irrespective of the point in which you intervene, the intervention does provide a therapy has an effect. The intervention does result in a separation versus an untreated control group. So when you look at the amyloid antibodies, if they intervene at MCI levels, they intervene at mild, you still see a separation even as they intervene further into the disease. There's no reason to think that that intervention at the moderate stage would not also result in a separation from a cognitive decline perspective in moderate patients as well relative to an untreated co ntrol. So I think if we believe the biomarkers are correlated to cognitive decline and the tau biomarkers, then it should follow that that would have an impact on cognitive decline. And I think as you look at all of the other programs that are presenting data, there's a significant emphasis on tau for the reasons that I said. The belief is that it is correlated to cognitive decline. So if you believe that, and these results reflect that directionally. The second question was about the different tau biomarkers. Yeah. So I don't know, Sandi, if you want to speak to that. Sure. So yes, as you rightly point out, we looked at total tau as well as the various forms of the phosphorylated tau proteins, which we did select multiple. So we used the p-tau181, p-tau217, p-tau231. In general, these are all biomarkers that have been associated with cognitive decline as well as brain atrophy. They are different isoforms. Frankly, probably the most common ones that have been reported in studies to date have included the p-tau as well as p-tau181, which has been closely linked, again, to cognitive decline and outcomes. What has been reported more recently in the literature is actually greater correlation, perhaps with the phosphorylated tau, the p-tau217, probably more so as a sensitive indicator compared to the 181 and 231. Overall, what really matters is that all of these are tracking in the right direction. They all reflect some shift in the impact on tau pathology that's occurring. And so if we look at the consistent pattern of the reductions across all of these, I think that that's a good measure in terms of the fact that LX1001 appears to be impacting the tau pathways in totality just looking at the totality of the measures. Super clear. Thanks so much. Nolan and I are going to let me add something to this. Yes, please. So what you're seeing here has some thing to do with the disease and the complexity of tau phosphorylation. What we're trying to, I mean, the goal is to have a convenient assay that sees only one phosphoepitope. So that you can reduce that to an ELISA that's easily done on a mass scale. Tau is phosphorylated on 50 different amino acids. So far, we've heard about two of those. So there will be a continued race of new ELISAs coming along until someone finds the very first site that's phosphorylated. But we probably have to go through all 50 before we get there. So this is going to continue to evolve. The next site that's coming now is the microtubule binding region. So this change in 181 to 231 to 217 is going to continue to be - that's going to continue to be a work in progress. The only way to see all the phosphorylation sites with mass spec, and that's just too cumbersome to do on a patient-by-patient basis. Got it. Thanks again. And your next question comes from the line of Mitchell Kapoor with H.C. Wainwright. Your line is open. Hey, everyone. Thanks for taking the questions. I appreciate that you can't yet provide context on the cognitive decline endpoints, but would you be able to just kind of comment on what you would expect for the rate of cognitive decline by this point with a natural history sample? And what would you expect in terms of separation with a gene therapy at some point in the future? And when can we see the next set of follow-up on these patients? Thanks for the question. I think the answer is complex because the patients are across the range of Alzheimer's disease, everywhere from MCI to moderate, and the rates of decline at each of those stages are different. So it's a very difficult question to answer because the subsets of patients are all very different from one another. Again, that was not a goal of this study. The goal of the study was to evaluate safety and evaluate biomarkers that are correlated to Alzheimer's disease pathology, and that's the focus of the data that we're reading out here. In terms of the effect that a gene therapy could ultimately achieve in cognitive decline, I think, again, the field is believing that tau is the most correlated to cognitive decline. The effect that we're seeing in many of the tau biomarkers is roughly equivalent to some of the commercially approved therapies, so if you believe in that correlation, you could theoretically see that cognitive decline could trend in the direction of some of the commercially approved therapies, but in this case, we've been able to do so without instances of ARIA. And that's a major step forward for APOE4 patients, where today the commercially approved therapies have up to a 40% risk of ARIA, yet they do not see statistically significant efficacy with those commercially approved therapies. So imagine that you can reduce tau in the way that they're impacting the disease in other therapeutic approaches, but then have the corresponding benefit in cognition and do so without ARIA. And I think that's the promise of what a potential gene therapy could deliver for this population. So again, it's a small study, dose-ranging, safety study, evaluating biomarkers, and that's the focus today. But I think we need to run a larger study to answer the questions on cognition. So I don't think we can reach any conclusion based on this very small data set. Makes sense. Is there a point at which we could see another set of follow-up from these patients? And then the last one from us is, given the dose-dependent expression, appreciate that you think the cohort four dose may be wanting to move forward with. Are there plans to test a higher dose potentially even? I think in terms of follow-up, we'll guide in our J.P. Morgan Healthcare Conference presentation about the milestones for 2025. I think additional follow-up for this program will be one of those milestones. So we'll provide an update on that. In terms of exploring higher doses, I think that is a possibility, but that's a decision we'd make alongside the partner that we would be taking the program forward with. So I think more to come on that, and that will be a function of a future update. Great. Thank you all. I will now turn the call over to Nolan for closing remarks. Okay. Well, thank you all for joining today. I appreciate the questions and taking the time to listen. I think we accomplished all of the goals that we had for this program for phase one. We achieved a safety profile that was compelling for this therapy with no reported events of ARIA. At the same time, we were able to see a dose-dependent increase in APOE2 expression across all patients out to 12 months. And that E2 expression resulted in a downstream impact on tau biomarkers and a stabilization of the amyloid biomarkers as well. So from our perspective, that was a win for this phase one. We did not expect to see an improvement in cognitive decline. We did not see it worsen from a safety perspective either. So I think all of those things are important factors to think about taking forward into the future study. As I mentioned earlier in the call, business development discussions are ongoing as well as engagement with the FDA. So we intend to provide an update on that in 2025. So more to come on this one, but thank you for joining, and we appreciate all of the questions. Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.