Great. Thanks, everyone, for joining. My name is Julian Pino. I'm an associate on Paul Matteis's team here at Stifel. I'm joined here by Marc Grasso and Gary Romano, CFO and CMO of Alector. Very excited to have you guys, and thanks, everybody, for tuning in. Let's go ahead and just dive in, I guess. First, Marc, maybe you could just provide an overview of the company, where things currently stand, and anything else that you want to highlight. Thanks again. Yeah, thanks, Julian, and thanks to Stifel for having us again at this event. Great to be here. At Alector, we're pursuing treatments for neurodegenerative disease and have an advanced portfolio, including two programs in the clinic that are progressing. The first is in a fully enrolled Phase III study for a setting called frontotemporal dementia. This is in patients with the GRN mutation. This Phase III study is anticipated to read out in Q4 of this year. This is a very significant unmet need. There are no currently approved disease-modifying therapies, and we, together with our partner, GSK, are really leading the effort to address this significant unmet need. Looking forward to that data later this year. We're also progressing our second clinical program, which is in Alzheimer's disease. This is also a sortilin-inhibiting antibody, as is our lead, latozinemab. This program is nearing completing enrollment in a Phase II study in early Alzheimer's disease. This is also together with our partner, GSK. In addition, at Alector, we're advancing a wholly owned portfolio of programs that we're very excited about. These are utilizing, in many cases, our proprietary Alector Brain Carrier brain shuttle technology. We're looking forward to providing additional updates around these programs in the near term, including on our proprietary and potentially best-in-class A-beta program, which is addressing Alzheimer's disease, as well as a novel GCase brain shuttle replacement therapy. This is an enzyme replacement therapy. We're happy to talk more about our portfolio. We're in a strong cash position with over $400 million in cash, and that's runway through at least 2026 and a year beyond our Phase III data readout for latozinemab in FTD-GRN patients and through clinical data events for additional programs in our portfolio, including our Alzheimer's program in the clinic, as well as we anticipate data for the Aß and the GCase program that are advancing towards the clinic. That's a brief overview, and happy to go into more detail. Yeah, of course. No, thanks so much. Looking forward to diving into the sortilin programs as well as the blood-brain barrier platform. I guess just really quickly, it would just be great to get any quick thoughts on the TREM2 program partnered with AbbVie previously. Obviously, Alzheimer's is extremely difficult. What can you say about AL002 and what you think may have led to the failure there? I know you said maybe some data is going to be coming out there in the near term, so just curious if you have any thoughts. Yeah. Hi, Julian. It's Gary. Thanks. Thanks for the invitation today as well. We shared that the INVOKE-2 trial, this is the Phase II trial, the TREM2 agonist antibody, that in that study, a treatment resulted in sustained target engagement and pharmacodynamic responses that indicate that we had treatment effects on microglial activation. However, we also disclosed that AL002 failed to meet the primary endpoint of slowing of Alzheimer's clinical progression. We measured that in a variety of ways, clinically, with the primary endpoint of the CDR Sum of Boxes and a number of other secondary clinical and functional endpoints. We also reported that there were no significant effects on Alzheimer's fluid biomarkers or PET imaging, demonstrating no treatment-related reductions in brain amyloid levels, for example, and no other indications that there was any real treatment effects on Alzheimer's biomarkers. As we previously reported, MRI changes that resembled amyloid-related imaging abnormalities were observed in the INVOKE-2 study and were apparently seen more frequently and with greater severity in those who were based on APOE4 genotype, with APOE4 homozygotes being most affected and therefore discontinued early in the study. We also have disclosed that we did not, as I said, we did not see any effects on amyloid PET or amyloid clearance, as indicated by either PET or various fluid biomarkers. Excellent. Yeah. On April 5th, we do plan to present more detailed results of the INVOKE-2 study during an oral presentation at AD/PD. That is the International Conference on Alzheimer's and Parkinson's Disease. That is going to be in Vienna in a couple of weeks. Got it. We look forward to sharing more details at that time. Excellent. Great. I think we can just go ahead and switch gears to AL001 then. You have the ongoing Phase III. I guess, really quickly, if you could just opine on, there's still sort of this debate on the biological hypothesis, whether SORT1 blockade is really sort of a viable way to increase granulin in areas of the brain that are deficient. I guess, can you just walk through a little bit of the rationale there and what underscores your confidence in this mechanism? Yeah, sure. I think the progranulin utilizes a variety of receptors, multiple receptors to signal and traffic to the lysosome, including PSAP, M6P, LRP1, and others. We have shown, and others, in animal studies that blocking the sortilin receptor does not interfere with lysosomal function, as you would expect if sortilin uptake of progranulin was required by itself for normal function. The hypothesis is that by blocking sortilin, we can elevate progranulin, which we have done robustly, showing a rapid and sustained elevation of progranulin two- to three-fold, which brings progranulin levels back to normal in these patients who are haploinsufficient due to having a loss of function mutation in the granulin gene. In terms of what gives us confidence, really, that comes from the Phase II study of AL001, in which, in addition to seeing the elevations in progranulin, we also saw changes in FTD-related biomarkers in the direction that you would expect to see if treatment were slowing the progression of FTD pathophysiology. That includes lysosomal and inflammatory biomarkers that we know are hallmarks of the pathological changes of FTD, as well as on GFAP and acidic protein, neurofilament light, and also region of interest MRI in the frontal and temporal regions in these patients. All those biomarkers had treatment effects that were moving them, as I said, as you would expect if we were slowing the progression of the disease. In addition, although it's a small study, we did a comparison of the clinical progression in this open-label study to historical data from the GENFI natural history study. That was a blinded propensity-matched analysis that showed that latozinemab treatment slowed the progression of clinical progression in patients with FTD granulin by 48% over one year of treatment. Based on all these Phase II findings, we have confidence that the effect on progranulin that we're seeing with sortilin blockade is sufficient to modify the pathophysiology and even to slow the progression of the disease. By the way, based on those Phase II findings, FDA granted us a breakthrough therapy designation for latozinemab for the potential treatment of FTD granulin. Got it. Super helpful. Yeah, I think, I guess, probably the main pushback some folks would give is, obviously, a small sample and comparing to natural history sort of always has its caveats. I guess, what underscores your confidence? I guess, as it relates to thinking about the Phase III, how do you sort of think about those points of critique when thinking about the Phase III design? Yeah. The Phase III design is very similar in terms of the biomarkers and outcome measures that we saw move. That study, the data that we reported on that study was after one year of treatment in 10 patients. Now we have over 100 patients with early symptomatic FTD granulin that were enrolled in the study, in the Phase III study. We're following them for two years. I think our confidence comes from the fact that we saw this highly consistent data across various types of fluid and imaging biomarkers and the clinical outcome. We're basically using the same approach, with one exception, which is that we're actually focusing this study on the early symptomatics. It was a little bit more open-ended in the Phase II study. We also included a small subset of patients, participants that are presymptomatic. That is, they have the loss of function mutation in the GRN gene, and they also met criteria for an elevation of neurofilament light. They were enrolled. They're not part of the primary analysis, but they will be included in sensitivity analyses. Got it. Makes sense. Appreciate that overview. You talk about you're enrolling 100 patients. Can you just remind folks, was that always the case? I know you sort of aligned with regulators on a new stats plan. Can you walk through that and what exactly you aligned on with FDA and how confident you are that if you were to succeed in this study, that this would be sort of fillable? Yeah. Yeah, thanks. Thanks. About a year and a half ago, I guess it was summer of 2023, we met with FDA to talk about a change in the analysis plan, not in the study itself, but in the analysis plan. That was based on the fact that the original study was based on data from the ALL FTD and GENFI cohorts dating back now more than five years ago. The new data had been published and came out and showed that in the, this was in a publication, that the variability of disease progression in the cohorts, in these observational cohorts, was less than what it had been in the earlier smaller sample. That led us to do a sample size re-estimation and saw that the variability was, in fact, less in the symptomatic cohort. We had really overestimated the variability when we came up with our sample size. Of course, the more variable progression is in the natural history of disease, the more potential noise you could have. Therefore, the reason you power up the study. We realized that. We also noted that the variability, both in the publication and in our sample size re-estimation in the presymptomatic subjects, was much higher than it was in the symptomatics, not surprisingly, since they did not show very much change. For that reason, we went to both FDA and EMA and proposed that we focus the primary analysis on the symptomatic subjects. Before that, the original plan was to combine the presymptomatic and the symptomatics. Both EMA and FDA were actually quite happy with this proposal. It gives you a more uniform population to look at and also agreed that with the sample size reduction, we were able to reduce the sample size, again, because we had reduced by focusing on the symptomatics, we had less overall variability. By the way, that variability does not mean that there is no treatment effect. This is looking at aggregate data, blinded aggregate data. I want to be clear about that. There is still plenty of room for there to be a treatment effect between placebo and active. That was the change that we made. That brought our target down to between 90 and 100 patients. We turned out to enroll 103 patients with symptomatic FTD granulin. Got it. No, makes sense. Yeah. I think you're anticipating sort of the next question, which is, obviously, when looking at sort of variability, I think there's always a sense on what does it implicate for the effect size? And could it mean that sort of these points are just overlapping and you're not seeing that separation? I guess, what gives you confidence that it's still viable and there's no concern about that, basically? Yeah. Yeah. I mean, the lower variability in disease progression increases our ability to determine a treatment effect with fewer patients. As I said, a blinded analysis of aggregate data does not really provide insight into effect size or differences between the treatment and placebo group. There is still, within the variability that exists, plenty of room for significant separation between placebo and the active arm. Makes sense. Great. Can you remind folks what you're powered for here? What were the assumptions that fed into this sort of target effect size? Have there been any changes made since you changed this target enrollment size? No. INFRONT-3 was designed to provide approximately 90% power to detect the 40% slowing of disease progression. If our trial assumptions hold, which so far, according to blinded sample size re-estimations they have, a 25% slowing of disease progression would be expected to be statistically significant. We feel like we're really well positioned here to deliver a meaningful data readout in INFRONT-3. I think I mentioned briefly that we had this meeting with FDA after having gotten the breakthrough designation. We had a meeting with FDA to discuss a variety of the biomarkers. We left there very encouraged. They agreed that the changes in either CSF and/or plasma progranulin would stand as confirmatory evidence, which is a specific regulatory term that means that with a single positive study and confirmatory evidence, it would be potentially, based on the BLA review, sufficient for approval. We also discussed with them a number of biomarkers, including NfL and GFAP and region of interest MRI, and also made the case that those should be considered predictive of clinical benefit. They also agreed that based on a BLA review, those biomarkers could be supportive of a clinical outcome. We were very encouraged by their sort of endorsement of these biomarkers and really looking forward to the readout later this year. Got it. Yeah. That's really helpful. I guess just on the biomarker specifically, we sort of have a path established with neurofilament by tofersen and SOD1. I guess, for example, in a scenario where if there weren't sort of stat-sig changes in PGRN, but you saw sort of changes in NfL or the data weren't sort of one-to-one totally consistent across the board, how confident would you be there? Yeah, anything to comment on that specifically? I just want to preface it by saying we haven't had that discussion directly yet with the agencies. I mean, that's the kind of discussion you have when you come with data in hand, like you said, as you described. We haven't discussed that specifically. Again, I think that we can read through a bit to say that FDA has shown regulatory flexibility. They seem to endorse the biomarkers that we think are most important and have pre-specified in our study. We are optimistic that if, as the scenario, something like you described where you just missed on the primary outcome, but you have strong biomarker support, they might exercise regulatory flexibility. Super helpful. Great. I think just one last question on FTD. What are your thoughts on commercial? How many patients are there? I guess, how frequent are these mutations within the broader population itself? Yeah. We estimate there's approximately 50,000-60,000 patients in the U.S. with frontotemporal dementia and about twice that number in the EU. We also recognize that this is an underdiagnosed disease that, because there are no approved therapies, genetic screening is not commonplace. It's also often misdiagnosed with other forms of dementia and depression and other aspects of the disease. Those may be underestimates. It's about 5%-10% of those patients that will have a GRN mutation. It's a meaningful market for a company our size. Understood. Great. Switching to AL101, just really quickly on that program, what are the main differences between that and latozinemab? What underscores your confidence sort of in boosting PGRN to treat Alzheimer's more broadly? Yeah. The difference is an indication. For those on the call, AL101 is a study in early Alzheimer's disease. It's a 76-week randomized double-blind placebo-controlled trial. We're going to assess the safety and efficacy of two doses of AL101 compared to placebo. The primary endpoints are Alzheimer's, CDR Sum of Boxes, and the usual other clinical and functional outcome assessments, and many of the same biomarkers that we used in our TREM2 study. The design is actually more similar to the TREM2 study design, which, by the way, even though it was negative, we were very, very pleased with the execution of that study, the clinical outcome measures, as well as the biomarkers performed and showed very consistent trajectories that were highly consistent with those reported previously in the early AD population. It gave us a very definitive answer on TREM2 there, but that we were hoping not to see. At the same time, very happy with the way that was executed. That is exactly what we were bringing to this progress AD study with 101. In terms of the rationale here, it is different than for FTD. FTD, as you pointed out earlier, is a haploinsufficiency. Patients have a single mutation with usually complete or close to complete loss of function. It is a lifelong deficiency. In Alzheimer's disease, there are some mutations that show partial, much more modest changes in loss of function mutations in the granulin gene that still increase the risk of Alzheimer's disease, not to the point that it is 100% penetrance, as you see in FTD. Nevertheless, even modest mutations in various analyses have showed increased risk of Alzheimer's disease. The idea here is not so much that we're normalizing progranulin levels to overcome a lifelong deficiency. It's that we're increasing progranulin levels in hopes of protecting against it. I should also mention that there's animal data that shows that increased progranulin expression and progranulin peptide seems to protect in some Alzheimer's mouse models. Here, the hypothesis is that if modest mutations can cause an increase in risk, increasing the levels two- to threefold above normal in this case could be protective against Alzheimer's disease. Got it. Super helpful. No, we're coming up close on time here, but did just want to give you guys a minute to talk about your blood-brain barrier platform. Obviously, a lot of interest in these types of technologies these days. What would you like to highlight from those programs? Anything to say about the interest in Aß and GCase specifically? Yeah. Yeah. Very excited. We do think it's a formative time in the field and for us with these approaches. We have a technology that stands out in several ways. We have a proprietary approach. It's a toolbox approach, which is versatile and tunable. We are using a transferrin receptor, a CD71 heavy chain technology as well in certain cases. This allows us to tailor for a range of cargoes that could be antibodies, can be enzymes, can be nucleic acids, siRNA, et cetera. We can have tenfold increases in brain concentrations, as we've demonstrated in animal models. We do this in a very customizable way. We can customize things like affinity, valency. We can do this in a way that allows us to really optimize the therapeutic window for our programs. As mentioned earlier in the call, we're advancing an Aß program that we believe has best-in-class potential. This is a program that has tailored affinity to transferrin to minimize side effect issues with transferrins. Anemia has been seen as a concern with some other brain shuttle approaches. Also, the best-in-class epitope for binding for plaque removal with the pyroGlu-3 Aß epitope. We also are tailoring the effector portion of the antibody as well to make sure that we're recruiting the microglia in to clear the plaque in an optimal way. We are looking forward to providing further updates on that program and also updates around our GCase program. Both of these programs are advancing to the clinic. We anticipate next year. GCase, as you may know, is a naturally occurring enzyme. It's unstable. It's short-lived. It's difficult to manufacture. What we're doing is really optimizing that with a brain shuttle so you can have the first potential neuropenetrant GCase replacement therapy. This has a range of applications extending from potentially GBA patients with Parkinson's disease to Gaucher patients and a range of significant unmet need. Very excited about those programs, as well as others that we're advancing with our proprietary Alector Brain Carrier shuttle technology. Excellent. Great. I think that about wraps up our discussion. Thank you both so much for joining us today. It was great to hear these updates. Thank you all for joining. Really appreciate it. Stay tuned for the next one. Thanks, Marc and Gary. Thanks, Julian. Bye now. Take care.