Good day, and thank you for standing by. Welcome to Alector's Q4 2023 earnings conference call. At this time, all participants are on 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 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 would now like to excuse me, turn the conference over to your speaker for today, Katie Hogan. Please go ahead. Thank you, operator, and hello, everyone. Earlier this afternoon, we released our financial results for the fourth quarter and full year 2023. The press release is available on our website at www.alector.com, and our 10-K was filed with the Securities and Exchange Commission this afternoon. Joining me on the call today are Dr. Arnon Rosenthal, Co-founder and CEO; Dr. Sara Kenkare-Mitra, President and Head of Research and Development; Dr. Gary Romano, Chief Medical Officer; and Dr. Marc Grasso, Chief Financial Officer. After our formal remarks, we'll open the call for Q&A. I'd like to note that during this call, we'll be making a number of forward-looking statements. Please take a moment to review our slide on the webcast, which contains our forward-looking statement disclosure, and we also encourage you to review our SEC filings for more information. I would now like to turn the call over to Arnon Rosenthal, Chief Executive Officer. Arnon? Thank you, Katie. Good afternoon, everyone, and thank you for joining Alector for our fourth quarter and full year 2023 financial results conference call. I'll begin by highlighting the broad mechanistic potential of our immuno-neurology candidates. Our candidates recruit microglia, the brain's primary immune cells, to combat neurodegeneration by containing multiple classes of misfolded protein, maintaining brain health and neuronal function, and supporting the maintenance of healthy synapses, astrocytes, oligodendrocytes, the blood-brain barrier, and the vasculature. By harnessing microglia, our candidates aim to comprehensively address the complex pathology of neurodegenerative diseases, potentially providing long-lasting clinical benefits across multiple disease stages. Our investigational drug candidates have the potential to be effective as standalone therapies or in combination with other treatments, particularly those targeting misfolded proteins. The broad disease-fighting mechanisms that our drugs activate, as well as the potential synergy between our immunoneurology candidates and therapies directed against misfolded proteins, has the potential to elicit a more potent therapeutic benefit with longer durability and better efficacy at multiple disease stages compared to current therapies against misfolded proteins. As we reflect on the past year, I am pleased to highlight that 2023 was marked by successful clinical execution and clarity around timelines for our advanced clinical development programs. We achieved significant milestone in our late-stage programs, reinforcing Alector's standing as a pioneer in immunoneurology. Importantly, we completed trial enrollment for our two lead programs. This includes the pivotal INFRONT-3 phase III trial for, of our progranulin-elevating candidate, latozinemab, in frontotemporal dementia with progranulin gene mutation or FTD-GRN, and INVOKE-2 phase II trial of our TREM2 candidate, AL002, in early Alzheimer's disease. In partnership with GSK, we also recently dosed the first participant in PROGRESS-AD, the phase II clinical trial of AL101 in early Alzheimer's disease. Furthermore, in February 2024, the FDA granted Breakthrough Therapy designation to latozinemab for FTD-GRN, marking another significant achievement. It is worth noting that although FTD is a complex disease clinically, we have developed a straightforward approach to correcting progranulin deficiency, the underlying cause of the disease. Collectively, these advancements move us closer to potential meaningful data readout this year and next. In January, we also further strengthened our balance sheet with the completion of $75 million follow-on financing, which Marc will touch on further. Later in this call, Sara will provide insight in our early research and development efforts, including Alector's Brain Carrier technology platform. Our commitment to addressing neurodegeneration remains unwavering, and with our advanced pipeline, strong cash position, we are well-equipped for meaningful value creation in the next phase of our growth. This year, we'll continue to focus on delivering and translating our progress into meaningful impact. An important event will be the anticipated data readout from INVOKE-2 phase II trial of AL002 in the fourth quarter. This will potentially be a major step forward in elucidating our immunoneurology hypothesis. Together with the support from our partners, we are committed to advancing neurodegenerative disease research, reflecting our firm belief in immunoneurology, in the immunoneurology potential. With that, I will turn it over to Gary to talk about our goals and expectations for our clinical development program. Gary? Thank you, Arnon. I'll begin with our AL002 program, the most advanced TREM2 program in clinical development for Alzheimer's disease. AL002 is a novel investigational humanized monoclonal antibody that binds to and activates TREM2, a key microglial receptor that senses pathological changes in the brain. Binding of AL002 to the TREM2 receptor triggers microglial signaling pathways, which increase microglial proliferation, survival, and function, enhancing the effectiveness of microglia to protect the brain against insults, including age-related neurodegenerative disease. We completed our phase I trial of AL002 in healthy volunteers, which demonstrated both dose-dependent target engagement and activation of microglia. In the trial, AL002 was also shown to be well-tolerated. Our ongoing INVOKE-2 phase II-B study of AL002 is a randomized, double-blind, placebo-controlled, common close design study of up to 96 weeks of treatment with AL002, in which 381 participants with early Alzheimer's disease were randomized. The study includes three doses of AL002 that demonstrated robust target engagement and increased microglial signaling in phase I. INVOKE-2 completed enrollment ahead of schedule in September of last year. The primary clinical outcome measure for this study is the CDR Sum of Boxes. We're also collecting secondary clinical and functional outcome assessments, including the ADAS-Cog13 and ADCS-ADL-MCI, from which we will derive treatment effects on the Integrated Alzheimer's Rating Scale or iADRS. The trial will also deliver a robust biomarker package, reflecting target engagement as well as treatment effects on microglial activity and Alzheimer's pathophysiology. Treatment effects on Alzheimer's pathophysiology will be assessed with CSF and plasma biomarkers of Aβ and tau, as well as both amyloid and tau PET. We'll also have biomarkers of astrogliosis, neuroinflammation, synaptic health, and neurodegeneration. We intend to use a proportional analysis approach with this study, which will enable us to use all the data collected in this common close design trial, meaning that it will include data from all participants out to 48 weeks, and also include additional longer-term follow-up from those participants who are in the study for up to 96 weeks. We also have a long-term extension where we remain blinded to treatment assignment, and thus can provide additional information on long-term safety and also on treatment effects on clinical outcome measures and biomarkers. As we reported last year at AAIC, a subset of participants in the ongoing INVOKE-2 trial have had treatment-emergent MRI findings that resemble the amyloid-related imaging abnormality, or ARIA, that has been observed with anti-amyloid therapies. These MRI findings are indistinguishable from ARIA with regard to the MRI features, incidence, timing of onset and resolution, relatedness to the number of APOE4 alleles, as well as to the frequency and spectrum of associated clinical manifestations. In the current trial population, that includes APOE4 heterozygotes and APOE4 non-carriers, analysis of the still blinded data shows an incidence of ARIA-E and ARIA-H of approximately 20%. Of those with ARIA-E, approximately 90% have been asymptomatic, and most symptomatic participants have had mild and self-limited presentations. Most relevant from a clinical perspective, the incidence of clinically serious ARIA, that is, those with ARIA-related SAEs, is just under 1% of all participants that have been dosed. An independent data monitoring committee reviews data from this trial regularly and continues to recommend that the trial proceed. Our goals for INVOKE-2 trial and for AL002 in the long term are to slow the progression of Alzheimer's disease by therapeutic restoration of microglial function. While one of the potential effects of TREM2 agonism may be to increase the clearance of misfolded proteins, including amyloid, we expect AL002 to also amplify the broader beneficial effects of healthy microglia on the brain. This includes maintaining synaptic connections, supporting astrocyte and oligodendrocyte function, preserving the blood-brain barrier and vasculature, and upholding immune tolerance. Thus, our expectation is that the restoration of microglial function by AL002 will reduce the brain's vulnerability to neurodegenerative disease, and that the INVOKE-2 trial will demonstrate treatment-related slowing of Alzheimer's disease progression, as demonstrated by a combination of clinical, functional, and biomarker readouts. Given the multiple mechanisms by which healthy microglia protect the brain against neurodegenerative disease, we hypothesize that by the end of development, AL002 may ultimately display stronger efficacy than current therapies that target individual misfolded proteins. Through its novel and complementary mechanism of action, we expect AL002 to be effective either as a standalone therapy or in combination with anti-amyloid therapies. Given that agonism of TREM2 has the potential to reduce the brain's vulnerability to neurodegenerative disease through these multiple downstream mechanisms. We believe that treatment of benefits of AL002 may manifest differently from what we have seen in the anti-amyloid antibody trials. For example, with regard to biomarker responses, lowering cerebral amyloid PET signal to the 20-30 centiloid threshold, which for anti-amyloid antibodies appears to be a necessary condition for clinical efficacy, may not be relevant to this mechanism of action that goes beyond amyloid clearance. Additionally, optimal disease stages for intervention may be broader. Unlike therapeutics targeting amyloid or tau, we do not expect the beneficial effects of healthy microglia to be limited to specific pathophysiological stages of disease, and thus AL002 has potential to benefit patients from preclinical Alzheimer's disease through advanced dementia. I'll now turn to latozinemab, our novel first-in-class progranulin elevating candidate and the most advanced therapeutic in clinical development for the treatment of frontotemporal dementia. You may recall that latozinemab has previously received both Orphan Drug designations for FTD and Fast Track designation for FTD-GRN from FDA. We are pleased to share that in February, FDA granted latozinemab Breakthrough Therapy designation for FTD-GRN based on our INFRONT-2 phase II clinical trial data. FDA's Breakthrough Therapy designation is granted to expedite the development and review of drugs that are intended to treat a serious condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint. With this designation, we look forward to continued productive conversations with the FDA, recognizing the unmet need for people living with FTD-GRN, a serious condition for which there are no FDA-approved treatment options available. In October 2023, we achieved target enrollment of the pivotal randomized double-blind, placebo-controlled INFRONT-3 phase III clinical trial of latozinemab, randomizing 103 participants with symptomatic FTD-GRN and 16 participants who were presymptomatic at risk for FTD-GRN. Our goal was to enroll 90 to 100 symptomatic participants, supported by feedback from FDA and EMA. We are actively progressing the INFRONT-3 trial in partnership with GSK and look forward to the pivotal phase III data readout following the 96-week treatment period. I'd like to now turn to AL101, our second product candidate in our progranulin portfolio that we are developing in partnership with GSK. Like latozinemab, AL101 is a monoclonal antibody that blocks sortilin to elevate progranulin levels. Its distinct pharmacokinetic and pharmacodynamic properties have potential to enable dosing regimens that may be more suitable for use in the treatment of larger indications, such as Alzheimer's disease. Our phase I study in healthy volunteers demonstrated that AL101 was well-tolerated and increased progranulin levels in plasma and CSF in a dose-dependent manner. In August 2023, Alector and GSK received FDA clearance of its IND application for AL101 in the treatment of early Alzheimer's disease. The rationale for treatment of Alzheimer's disease is that genetic variants that result in modest reductions of progranulin levels are associated with an increased risk of developing Alzheimer's disease. Conversely, in animal models of Alzheimer's disease, elevation of progranulin has been shown to be protective. In February of this year, the first participant was dosed in the PROGRESS-AD study of AL101, which is being operationalized by our partner, GSK. PROGRESS-AD is a randomized, double-blind, placebo-controlled phase II clinical trial of AL101, enrolling approximately 282 patients with early Alzheimer's disease at multiple sites globally. The 36-week study is designed to assess the safety and efficacy of two dose levels of AL101 compared to placebo. Participants are randomized to one of three dose groups, receiving AL101 or placebo intravenously. The primary endpoint of the study is disease progression, as measured by the CDR Sum of Boxes. The trial also employs other clinical and functional outcome assessments and biomarkers. We look forward to sharing additional information on PROGRESS-AD as the trial advances. With that overview, I'll now turn the call over to Sara to provide an update on our early research pipeline. Sara? Thank you, Gary. We are making meaningful strides in progressing our research portfolio to fuel our development pipeline and set the stage for our long-term growth. Our drug discovery engine is fine-tuned through a decade of deep biological exploration and expertise in neuroscience, as well as strong expertise and experience in antibody, protein engineering, and preclinical development. We have also developed a modular and scalable target discovery platform, which seamlessly integrates genetics, multi-omics, and in-house generated wet lab data to uncover novel targets. The system further improves predictions through machine learning-based target identification, multidimensional functional validation, and data integration with AI-based analysis. Our overall integrated approach allows us to move swiftly from target identification to the development of late-stage, first-in-class immunoneurology drug candidates. In addition to our target and drug discovery engine, we have also made progress on our proprietary blood-brain barrier technology. While our late-stage clinical candidates show brain penetration and target engagement, we are developing a proprietary, versatile blood-brain barrier technology called Alector Brain Carrier, or ABC, to strive to lower efficacious doses with favorable safety and efficacy and enable delivery of additional novel drugs into the CNS. We intend to selectively deploy our technology in a fit-for-purpose manner on our next-generation programs that are currently in our early portfolio. ABC technology is a toolbox approach incorporating a suite of single-chain variable fragments, antigen-binding fragments, or variable heavy chain domains that bind to targets at the blood-brain barrier, such as transferrin and CD98 heavy chain with varying affinities. We have been able to achieve greater than tenfold increase in brain concentrations of multiple cargos and demonstrated deep brain penetration to cell types of interest, like neurons and microglia. The modular nature of this technology allows the affinity, valency, and format of the final therapeutic to be harmonized with the mechanism of action and cell type specificity of the associated cargo. We are also leveraging our ABC technology to advance the development of protein replacement therapies for neurodegenerative diseases, which aligns with our focus on genetic risk factors. Our technology's adaptability is demonstrated through versatile bispecific formats, complemented by customizable Fc adaptations for optimized effector function, half-life, and single-chain configurations. Based on the translatability of preclinical safety and efficacy studies, our technology appears to exhibit a favorable safety profile, even when actively engaging with Fc. We look forward to sharing more details about our innovative research portfolio, including our Alector Brain Carrier technology, during a virtual event later this year. I'll now turn it over to Marc to provide an update on our financial results. Marc? Thank you, Sara. As summarized in our fourth quarter and full year 2023 financial results, which we made available after the market closed today, we are in a strong cash position to deliver against our strategic objectives. We continue to focus on fiscal management and program prioritization, and as of December 31st, 2023, our cash, cash equivalents, and short-term investments totaled $548.9 million. Strengthening our financial position, we completed a follow-on financing in January of this year, raising $75 million in gross proceeds. Inclusive of this raise, our cash runway is now through 2026, approximately a full year beyond the expected FTD-GRN and pivotal phase III INFRONT-3 data readout, and approximately two years beyond our TREM2 phase II INVOKE-2 data readout. Further, we are now also in a position to selectively accelerate investment in our innovative proprietary portfolio, including programs enhanced by our proprietary Alector Brain Carrier technology platform. We appreciate the support of significant new investors as well as participation from our existing shareholders. Now, turning to our operating results. Collaboration revenue for the fourth quarter was $15.2 million, compared to $14.4 million for the same period in 2022. Collaboration revenue for the year was $97.1 million, compared to $133.6 million in 2022. Total research and development expenses for the fourth quarter were $47.7 million, compared to $54.5 million for the same period in 2022. Total research and development expenses for the year were $192.1 million, compared to $210.4 million in 2022. Total general and administrative expenses for the quarter were $14.9 million, compared to $15.4 million for the same period in 2022. Total general and administrative expenses for the year were $56.7 million, compared to $61 million in 2022. For 2024, we estimate our collaboration revenue to be between $60 million and $70 million. Our anticipated total research and development expenses are estimated to be between $210 million and $230 million, and total anticipated general and administrative expenses are estimated to be between $60 million and $70 million. In December, Alector hosted two virtual research and development events discussing our TREM2 and progranulin programs in detail. The events included presentations from leading scientific and clinical experts. We encourage those who didn't have an opportunity to participate in the live events to watch the replays located under the Investor Events and Presentation section of our website. We remain focused on advancing our novel portfolio and Alector Brain Carrier technology to treat neurodegenerative diseases. We look forward to providing additional updates as we advance our work. That concludes our prepared remarks for today's call. Operator, you may now open the line for questions. Thank you. As a reminder, if you would like to ask a question, please press star one one on your telephone. Please wait for your name and company to be announced before proceeding with your question. One moment while we compile the Q&A roster. Our first question today is coming from Yaron Werber of TD Cowen. Your line is open. Hi, this is Brendan on for Yaron. Thanks very much for taking the question. Just a couple quick ones from us. Actually, first on the Brain Carrier program, just wondering if you might be able to give us a little bit more color around kind of just the broad approach to the platform. I mean, you mentioned transferrin and CD98. Are you kind of, at this point, planning to kind of choose one and use that across the board for all the BC programs, or are you kind of going to go an indication-by-indication basis? And then I guess, really on the ADP027 asset that you called out in the press release. Kind of just wondering what drove the decision to target GPNMB, and maybe how applicable that target would be kind of to the broader Parkinson's population? Thanks very much. Thanks. I'll just address the question about the blood-brain barrier technology, and then I'll pass it to Arnon to answer your question on GPNMB. Briefly, you know, our blood-brain barrier approach, as we said, employs a very versatile Brain Carrier technology, and we are targeting blood-brain barrier proteins, both TfR and CD98 heavy chain. At this moment, we are going after both these targets and applying them across both our second generation efforts for our current late stage programs, as well as our new novel sort of target molecules in research. And certainly do not, you know, have any intent initially to choose one over the other. We will depending on the best approach for each target and each molecule. Again, we are using, you know, very adaptable technology, which allows us to customize for therapeutic affinity, valency, et cetera. We've got bispecific formats and customizable Fc adaptations that allow us to tweak effector function as well as optimize half-life on the molecule. So, our approach currently is to, you know, try both these targeting approaches, trafficking approaches, both for our late-stage programs as well as for our novel targets. And maybe Arnon can share his thoughts on our ADP027 program, the GPNMB. Yes. So yeah, we do think that GPNMB targeting will be applicable for sporadic Parkinson's disease. GPNMB is a lysosomal regulator. It's a risk gene for Parkinson's disease. There are both risk and protective variants, and we developed a drug that maybe can exceed the protective variants. And we think that sort of lysosomal pathology is a general feature in Parkinson's disease, and GPNMB is interacting with LRRK2, interacting with GBA, two other risk genes for Parkinson's disease. It's upregulated in multiple types of sporadic PD. So we do think that it will be applicable for any type of Parkinson's disease. All right. Thanks very much. Thank you. One moment for the next question. Our next question today will be coming from Paul Matteis of Stifel. Hi, this is Julian on for Paul. Thanks so much for taking our question. I guess on AL002, the TREM2 program, with the readout expected towards the end of the year, the trials anticipated to run for about a year, at least at a minimum in terms of follow-up. I guess, what gives you guys confidence that this will be long enough to separate from placebo? And do you anticipate at all that there will be a significant group of patients out to two years? And any other color on how the overall data will be analyzed or shared in a top line would be super helpful. Thank you. Yeah, hi. Thanks for the question. This is Gary. So the study, as you heard, is a common close design, in which all patients will stay in the trial for up to 96 weeks, and then roll over into long-term extension, and that is until the last patient out reaches 48 weeks, at which time all patients will roll over into the long-term extension. And so we will have data, not only will we have data out to 48 weeks on everybody, but we'll also have data out to... We'll have, for example, clinical outcome assessments out to 96 weeks, on a good subset of patients. We're planning to use an analysis method called a proportional analysis method or proportional MMRM, for example, which uses all of the data. So it's not just the time to event at one time point, but it includes data at all time points. It's a way of getting the most out of your data by using all of the data and that's our plan for the analysis for the primary analysis. You asked a question about do we think this is enough time to see treatment effect? You know, we're looking at treatment effect in this study as AbbVie and Alector designed the study in order to be a biomarker-rich study that will look at the totality of the data. So looking to see that we can slow Alzheimer's disease through a combination of clinical, functional and biomarker readouts. And we're gonna have a very robust biomarker package that includes not only what we originally intended, which would be amyloid and tau PET substudies, but also now with the acceleration in validation of phospho-tau assays, we'll be looking at p-tau217 and tau aggregates in plasma on all patients. So we feel confident that we are going to, through this totality of this data, be able to determine whether we're slowing the progression of Alzheimer's disease, which is what the original design was intended to do. Excellent. Thanks for the color. Thank you. One moment for the next question. Our next question will be coming from Jeffrey Hung of Morgan Stanley. Your line is open. Hi. Hi, this is Michael on for Jeff Hung. Thank you for taking our question. For Invoke, how do you expect levels of soluble TREM2 to look at for patients at baseline with pre-clinical AD versus maybe a little bit more progressed dementia? Like, does a higher baseline soluble TREM2 level, like, imply higher chances for, like, a pharmacodynamic effect? So, first, let me just, this is Gary again. We're just to clarify, we are enrolling patients, as you said, with early Alzheimer's disease. We are not enrolling, for example, just those with genetic variants, like the R47H variant. You know, we don't believe that the baseline levels of soluble TREM2 necessarily. We don't really know whether that's gonna predict a pharmacological effect, but what we would expect in our study is that the binding of AL002 to TREM2 causes internalization of the receptor. And this actually causes a reduction in soluble TREM2, because what we're basically doing is reducing by binding and internalizing the receptor, we're lowering the levels of microglial membrane TREM2, which and that reduces the amount of the cleavage product, soluble TREM2, which is constitutively cleaved from TREM2, right? So we will see, as we saw, we intend to see, as we did in phase I, a reduction in soluble TREM2. You know, again, there's different ideas about soluble TREM2 and what its role is. We believe that primarily it's really a marker of membrane TREM2. You know, there's a fair amount of data out there that suggests that soluble TREM2 levels, which again are reflecting the amount of TREM2 in the membrane, correlate, you know, as they are higher, they correlate with better outcomes or progression of disease, of Alzheimer's disease, slower conversion from MCI to Alzheimer's disease, slower progression of brain volume loss. So again, but that is a function basically of having greater TREM2 activity, and our antibody increases TREM2 signaling. Thank you so much. Really helpful. Mm-hmm. Thank you. One moment for the next question. Our next question will be coming from Pete Stavropoulos of Cantor Fitzgerald. Your line is open. Hi, Arnon and team. Thank you for taking my questions. So first one, you know, I believe that, you know, for the INVOKE-2 study, the placebo rolls over, you will start. You know, you will be starting them at a lower dose than those in the original randomized the active arm, and then, you know, titrating them upwards. Can you just discuss the timeline for the titration? And will you be able to capture any data points, you know, especially biomarker wise, you know, that could suggest that the starting dose is therapeutically active? And if so, you know, what would be the key biomarker or biomarkers you believe may be informative at that time point? Yeah, thanks, Pete. A good question. So you're right, we are. So just to clarify, in the long-term extension, all patients that were on active doses in the double blind will roll over to the same dose and continue in the long-term extension. Those that were originally randomized to placebo will now be titrated up, started on active, beginning with a, at a lower dose. That's right, 6 mg per kg, and increase, and they will be dose escalated every two months. And one reason for doing this is to learn more about the potential mitigations for the ARIA-like signal that we're seeing. As you know, in some of the anti-amyloid therapeutics, there's been, you know, data that suggests that starting at a lower dose and/or titrating more slowly than we did in this double blind study could be mitigating. So that's one advantage. We do believe that this slow titration, though, is actually gonna help us in another way. And not only to learn about mitigation for ARIA, but also help us to in a sense, it will... This long-term extension, which, by the way, we invested with AbbVie to keep this blinded to the original treatment assignment. This will give us an opportunity to continue to follow patients beyond the double blind into the long-term extension, to look for not only for safety, but also to look for treatment effects on biomarkers, and most importantly, on clinical outcome measures. So, you know, for example, with the common close design, some of the patients will have a year, only a year of follow-up data on clinical outcomes. But in the long-term extension, which will really essentially be a randomized start design, we'll be able to look for differences between the original placebo group and the active dose groups. In the long-term extension, we'll be able to look at those clinical outcome assessments and differences between the placebo and actives in that long-term extension. All right, thank you for that. And, you know, one question on the, on the phase II for AL101, you know, originally initiated with GSK. You know, just, you know, looking at the study design, I see that there are two undisclosed doses being evaluated. You know, how did you select those doses? You know, if you can tell us, you know, was it based on a certain level of, you know, PRG, PG- PRGN increase in the phase I? And, you know, are you trying to keep it above a certain threshold or, or below a certain level? Yeah. Sarah, I'll start, maybe Sarah, if you wanna, if you wanna chime in on the PK here, that behind it. Yeah, so we have two doses. We have a maximal dose, that gives us maximal, you know, elevations of progranulin. And we also chose a somewhat lower dose. And those, the... I'm not sure how much of this we've disclosed in terms of the actual doses and the randomization ratio, so I'm gonna have to defer to Mark or Sarah as to whether we're- Yeah, I think it- disclosing that at this time. Thanks. Thanks, Gary. Yeah, agreed, Pete, we haven't disclosed their actual doses or the selection, but mostly, the doses were selected based on the PK and PD data that were generated in our phase I, single and multiple ascending dose studies, and based on progranulin levels, of course. So it was the elevation of progranulin in plasma and CSF that was modeled and, based on this, the two doses were selected. We haven't really shared the exact doses or the exact criteria for the selection of the doses. Okay. Thank you for taking my questions. Thank you. One moment for the next question. The next question will be coming from Greg Harrison of Bank of America. Your line is open. Hey, good afternoon, thanks for taking the question. What endpoints that you'll report from the INVOKE-2 trial do you think will be key to understanding the benefit of AL002's various mechanisms beyond amyloid reduction and potentially showing differentiation versus anti-amyloid antibodies? Yeah, thank you for that question, Greg. So, you know, just to remind everyone, you know, the mechanism here is, we believe is the therapeutic restoration of microglial function that will slow disease progression. And as you mentioned, that includes, may include enhanced clearance of misfolded proteins, like amyloid, which we know is one of the important functions of microglia. But that there are also a number of other, beneficial effects of microglia, that they do in normal maintenance to preserve brain health, reduce vulnerability of the brain to insults, including, age-related neurodegenerative diseases. And I think we mentioned those a couple times in the presentation. So, in this study, therefore, we are—and again, this is a novel mechanism, and we think that it's important to realize that through these various downstream mechanisms of healthy, you know, that are in play because of healthy microglia, there are a number of things we can measure, and we're going to be measuring in the study, including outside the typical Alzheimer's biomarkers that we mentioned, Aβ and tau, both in plasma and with PET scans. We'll also be measuring astrocyte, you know, effects on astrocytes and synapses and oligodendrocyte function, et cetera. I think the totality, really, what a decision is going to be based on, though, is whether or not we're slowing the progression of Alzheimer's disease. And so all of those mechanisms, if to be meaningful, have to add up to a slowing in the progression of disease. And that will probably be best measured by clinical outcome measures and also by biomarkers. And of those biomarkers, not only Aβ, but very importantly, the tau biomarkers. 'Cause we know that tau changes in tau and tau aggregates travel or, you know, correlate most closely with disease progression in AD. And so we'll be looking at the clinical outcome measures. We'll be looking at the Alzheimer's biomarkers, particularly, for example, plasma p-tau217, and also looking at tau aggregates with other tau phospho assays, like the microtubule binding region assay. I wanna emphasize, you know, this study is powered for clinical effect of about 40%. That's a big effect. So, you know, we may or we may not see a clinically significant effect of that size in this relatively small phase II study. But again, the original design was intended not to have a decision made on the primary clinical endpoint, but on the totality of the data, particularly, the biomarker data that I mentioned. Got it. That's, that's really helpful. Thanks. Thank you. Thanks, Greg. One moment, and our next question will be coming from Corinne Jenkins of Goldman Sachs. Your line is open. Hi, this is Palak on for Corinne. Just one for us. Could you please share what's embedded in the cash runway guidance with respect to clinical activities, more so beyond the near-term clinical events? Yeah, thanks for the question. So I think the question was around what’s included in the cash runway guidance. So, the cash runway guidance, as noted, is now through 2026, and that's two years post the anticipated TREM2 data and also approximately a full year beyond the anticipated FTD-GRN phase III data, and also allows us to accelerate our investment in our blood-brain barrier technology platform and also our proprietary early-stage pipeline. Importantly, it is conservative in the sense that we're not including any milestones from partners, including the potential significant opt-in from AbbVie at the end of the completion of the phase II. It does include a full spend on AL002 through the phase II completion. Also, continued spend on that program for the extension study and spend on the FTD-GRN phase III, and also spend on the recently commenced AL101 phase II for Alzheimer's disease. So those are the major components in addition to you know continuing to progress our blood-brain barrier platform and early pipeline. Understood. Thank you. Mm-hmm. Thanks for the question. Thank you. One moment for the next question. Our next question is coming from Carter Gould of Barclays. Your line is open. Hey, this is Leon on for Carter. Thanks for taking my question. So we have two on INVOKE-2. So at this point, do you have alignment or understanding with AbbVie on what a potentially good profile could look like on the readout? And in terms of your update on achieving 90% enrollment in the OLE from INVOKE-2, now, that's against the backdrop of having the ARIA-like effects you've seen. So we wanna get your thoughts here on the implication of, you know, getting 90% enrollment in the OLE. Is there some nuance that we're missing or anything that you'd like to highlight in terms of what this could tell you about the safety and tolerability profile? Thank you. Yeah, well, to the latter question, just that, that's 90% of those that were eligible to roll over out of the 90-60 common close design study. And, you know, I mean, I think that we believe that reflects, you know, an interest in patients to continue. You know, there are increasingly other options, like they could start taking lecanemab. But most, you know, if you hear, you know, 90% or so are rolling over and staying in the long-term extension, which we, you know, interpret positively in terms of tolerability and potentially, you know, other effects of the drug. But we can't discuss. We We really can't, you know, speculate on at this point. I'm blanking on your first question. I'm sorry. Can you just remind me in the beginning? I'm sure I'll remember it. You were asking... Oh, I know, I remember now, about the readout. Right. Yeah, yeah. So, so sorry, sorry. I just had a blank out there. So yeah, so as I mentioned, we've been aligned with AbbVie really from the start on the how we designed this study. You know, that we're really looking at the totality of the data to tell us whether we're slowing the progression of Alzheimer's disease, which would, you know, to make a decision on what happens next with this compound and whether it progresses. So that includes, you know, that includes, as I said, you know, clinical outcome measures, and it includes some functional measures, and it includes a lot of biomarkers. So, particularly, you know, we're thinking that we'll be really focusing on those Alzheimer's biomarkers of Alzheimer's pathophysiology to tell us that we are seeing some slowing of the disease progression. Gotcha. Thank you. I hope that answers your question. Yep. Thank you. One moment for the next question. Our next question will be coming from Myles Minter of William Blair. Your line is open. Hey, just a couple on INVOKE-2. Are there any sort of material differences that you're seeing in the ARIA incidence rates between the double-blind portion of INVOKE-2 and the long-term open-label extension? I would assume that ARIA goes up if you're having placebo switch to active drug in that arm. That's the first question. The second one is, you're measuring tau in all of those patients. Are you gonna do a primary analysis by which you stratify by tau burden, similar to what Eli Lilly did and others have done in a post hoc setting? Thanks. Yeah, thank you. To the second question, we will have the capability of doing that post, you know, we didn't stratify the study based on tau, but we will be able to look with plasma p-tau at measures in order to, you know, in order to see whether there are differential effects based on baseline tau, not the baseline tauopathy. Yep. And I should be in some other direction. And your first question was around the ARIA signal. Yep. So, we've shown, we've shared this data, the imaging, the MRI, the MRIs themselves, the clinical vignettes, these patients, and truly, this looks indistinguishable from the ARIA that has been described with anti-amyloid antibodies, within every regard with regard to its timing of onset. For example, we see this early in treatment, and then it really tapers off. You know, the time to onset and resolution, the relatedness to number of ApoE4 alleles, the MRI features themselves and the clinical manifestation. So it really, we really, you know, we don't see any differences, and we've shown it to a number of the ARIA experts, who have also said that this is really indistinguishable. I don't think we see any difference between the main study and the extension study either, Myles, to your question. Okay. So- Uh, yeah. No difference from the 19%-23% that you reported at AIC- No, no, no, no, no ... compared to your mice? Yeah. No, sorry, sorry. We, you know, we're blinded to who's who in the study. But, you know, so far, we have seen very little ARIA in the long-term extension. So, that- Yeah. Also earlier days with the extension study, Myles. So, you know, to try to- Mm-hmm ... draw inferences from those percentages would be, you know, difficult. Yeah. Cool. Thanks for the questions. Yep. Yeah. Thank you. One moment for the next question. Our next question is coming from Neena Bitritto-Garg of Deutsche Bank. Your line is open. Hi, it's Aravinda on the line for Neena. Thank you for taking our questions. So on the ABC technology, can you discuss how your transferrin approach differs from other transferrin-based delivery platforms? And then also on INVOKE-2, given what you know about the AL002 mechanism, which biomarkers do you see as being most likely to be correlated with improvement on CDR Sum of Boxes or any other clinical end points? Thanks. So I can start with the ABC technology, and then Gary can address your second question. In terms of our BBB approach, it employs a versatile blood-brain barrier carrier technology, which uses a suite of fragments that target both TfR and CD98 heavy chain. What we found is that thus far, we're getting about tenfold increases in brain concentrations utilizing these, these multiple cargoes. I think what's unique about our technology is that it is, an adaptable technology, and it's sort of modular, and it's customizable, based on the sort of the requirements of therapeutic affinity, valency, and format, and we can match that to a variety of, cargoes. We use bispecific formats, and we are also able to customize and make adaptations to the Fc portion, and have been able to sort of tweak a variety of ranges of effector function as well as half-life. As we said in the call, in our safety and efficacy studies in non-human primates thus far suggest a favorable safety and efficacy profile, even when we have Fc engagement, so. And we will be, by the way, we will have a webinar. The date's not set, but sometime this summer, which we'll, you know, we'll go into a lot more detail on our technology, so please do join at that time. And I'll pass it to Gary. What was it? What was that question? I'm sorry. I didn't hear it. Yeah. So just for INVOKE-2 and, given what we know about the AL002 mechanism, which biomarkers do you see as being most likely to be correlated with improvement in CDR Sum of Boxes or more generally, clinical outcome? Oh, yeah. Yeah. Sure, sure. Well, again, that would be the biomarkers of Alzheimer's pathophysiology. Most importantly, I think the tau biomarkers, both. We will have tau PET, which will be a tau PET sub study. But we will also have plasma biomarkers on everybody in this study. So p217 and hopefully microtubule binding region assay as well. So this will, you know, this will give us a... That's the, really, the tau biomarkers are the ones that correlate most closely with clinical outcomes, and really, can be seen as, I think, as, you know, sort of a, you know, summing up the effects, all these hypothetical effects of, of healthy, of benefits of, of healthy microglia, on, slowing the disease progression. All right. Great. Thank you, and congrats on the quarter. Thank you. Thank you. One moment for the next question. Our next question is coming from Thomas Schrader of BTIG. Your line is open. Good afternoon, this is Tom on for Tom. So for the ongoing phase II PROGRESS-AD study, is there a reason to perhaps stratify these patients based on baseline progranulin levels for any possible sub analysis in future? Thank you. Yeah, thanks for the question. We did not do. We're not doing that, and that's because it, in you know, the part of the evidence in favor, or in support of this mechanism is that mutations that cause even very modest effects in progranulin levels increase the risk of Alzheimer's disease. And so we didn't believe it was, you know, it would be necessary. And our hypothesis is that this would be effective in slowing disease progression, regardless of your baseline progranulin levels. There's also animal data, which maybe Arnon may wanna speak more to, that shows that in various animal models of Alzheimer's disease, that just elevating progranulin itself is protective against disease, you know, disease progression. Great. Thank you. One moment for the next question. Our next question will be coming from Ananda Ghosh of H.C. Wainwright. Your line is open. Hey, hi. Congrats on the quarter. You know, given the biology of TREM2, and from your own ARIA data, I think, you know, there's little doubt that experts, you know, believe, there's little doubt on the fact that the TREM2 might be involved in plaque removal. However, one question which I have, and, you know, that's based on lecanemab and donanemab, and also a lot of questions on tau, tau biomarkers today here. You know, given the data from those two trials and the recent publication validating plasma, you know, p-tau217, you know, do the MRI data, you know, the tau PET, the tau PET Aβ data, along with the plasma tau biomarkers, puts you into a position where you can negotiate an accelerated approval pathway, which strategically might be very similar to the lecanemab approach. So that's the question. Thank you. Yeah. Thank you. So if I understand your question, you're wondering whether based on changes or treatment-related changes on tau PET or on tau biomarkers, could that be the basis of an accelerated approval approach? Right. If there- If there is, you know, a clear sign that there is, you know, a remarkable change in the plasma tau biomarker based on- Yeah. The plaque removal, is there a potential for accelerated approval pathway similar to Kisunla approach? Yeah. I would never say no, and I would say that, you know, when we open this up and we see what we have, based on the robustness of the findings, you know, we would certainly, you know, if we thought that it was robust enough, we would certainly consider that. You know, we've also had questions about, you know, well, if we see very significant amyloid lowering, could that itself, could that also be, you know, and again, I think, you know, way of going to at this differently. That's not the original intention of this trial. But of course, we, when we open it up and we see what we have, if we think that there are potential paths forward, we will certainly explore them. Got it. Thank you. Thank you. And our final question for today will be coming from Graig Suvannavejh of Mizuho Securities. Your line is open. Greg, are you there? Your line is open. I would now like to go ahead and call and turn the call back over to Marc Grasso for final remarks. Thank you, operator, and thanks, everyone, for the thoughtful questions. Before we end the call, I'd just like to share that we'll be participating in a number of upcoming conferences, including TD Cowen's 44th Annual Healthcare Conference on March 5th in Boston, Leerink's 2024 Global Biopharma Conference on March 12th in Miami, Barclays Global Healthcare Conference on March 13th in Miami, and Stifel CNS Days March 19th. Thank you again for your time and attention. We'll now conclude today's call. This concludes today's conference call. You may all disconnect.