I'm pleased to introduce Dr. Arnon Rosenthal, CEO. Thank you for attending. Let's start off with a brief introduction of yourself and the description of the company, you know, why Alector was founded, the company thesis, and your approach to drug development. Thank you for inviting us and welcome, everyone. As Pete mentioned, I'm Arnon Rosenthal. I'm the CEO and co-founder. I've been in the industry for over 40 years, initially at Genentech Roche for 16 years, then started two other companies, Rinat Neuroscience, that developed the CGRP antibody drugs that Teva is now selling, and then Annexon Bioscience that's developed multiple drugs for neurodegeneration. For the last 10, 11 years, Alector is my life. Alector was created in order to try and cure neurodegenerative disorders. As you know, neurodegenerations are really one of the last major unmet medical needs. One in six people in the world has a brain disorder, including 50 million people with dementia, 10 million people with Parkinson's disease, millions of people with frontotemporal dementias, with ALS, with multiple sclerosis. The company was created to try to address this major unmet need. We are doing it with three major approaches. We are trying to remove misfolded proteins, which are the hallmark of most, if not all, neurodegenerative diseases. We are trying to replace damaged proteins, which are causing many diseases or are missing and causing the diseases like lysosomal enzymes. We are trying to cure or to repair immune cells and nerve cells which are damaged. Our pipeline really reflects this strategy. We have two late-stage programs that are designated to replace missing proteins. This is drugs that replace progranulin. Progranulin is an immune regulatory and survival factor for multiple types of nerve cells. Loss of function of progranulin actually causes multiple neurodegenerative diseases. If you lose 50% of the normal level of progranulin, you are invariably developing frontotemporal dementia before the age of 60. If you lose a modest level of progranulin at the range of 10% - 15%, you are at an increased risk to develop Alzheimer's disease, Parkinson's disease. You have an accelerated rate of ALS progression. You can develop late, which is another prevalent type of dementia that's typified by TDP-43. You have accelerated development of sporadic FTD. Progranulin loss of function is a unique universal risk gene for Alzheimer's for neurodegeneration. We developed a drug that elevates it. We are in a pivotal phase III with one disease and just in advanced stages of phase II in another disease. This is replacing a missing protein. We have multiple preclinical programs that are designed to remove misfolded proteins. We have an anti-ABETA drug that's linked to our brain carrier (shuttle) platform. We have an anti-Tau antibody that's linked to brain carrier (shuttle) platforms. We have an siRNA against Tau that's linked to our brain carrier (shuttle) platform. We have an enzyme replacement therapy, GBA, which we'll talk about for Parkinson's disease, again linked to our brain carrier (shuttle) platform. This year is going to be a major pivotal year for us. In the middle of Q4 this year, we'll have our phase III pivotal study that, if positive, will lead to rapid BLA and approval. Next year, we are going to complete our second phase II, a phase II study in Alzheimer's disease. By 2026, we are planning on introducing two new drugs to the clinic. All right, thank you for that. I guess you mentioned that you have one lead program in FTD driven by progranulin mutation. Can you just help us understand how many patients there are actually and how prevalent it is and how many patients in the U.S. and, let's say, the EU? Our most advanced program is treating frontotemporal dementia, which is the largest form of dementia for people under the age of 60. It's a very aggressive, lethal form of dementia. It progresses three times faster than Alzheimer's disease. It hits people in their 40s and 50s, and people die within seven to nine years after diagnosis. In a significant subset of these patients, the disease is caused by a single mutation in the progranulin gene, a loss of function mutation. There are 50,000 - 60,000 FTD patients in the U.S., about 110,000 FTD patients in the EU, and up to 10% of them have the progranulin mutation. In the EU and U.S., there are up to 15,000 or 17,000 patients with the mutation. These are symptomatic patients. There are four to five times more pre-symptomatic patients that are destined to develop the disease. Okay. You are developing latozinemab for FTD. You know, just describe its mechanism of action and the rationale behind. As I mentioned, the frontotemporal dementia that's caused by progranulin mutations is associated with 50% of the normal level of progranulin. We developed a drug that elevates progranulin back to normal level. The way our drug does it is by blocking a degradation cascade of progranulin. What happens in these patients is they make half of the normal level of progranulin. Once you block the degradation of progranulin, the protein stays in the brain two to three times longer, and you compensate for the reduced production by increased residence time. What we do is very similar to what the SSRI inhibitors do. SSRI inhibitors block the reuptake and degradation of serotonin and norepinephrine. By that, they increase the time the neurotransmitters reside or spend in the brain by two to three fold. This is what leads to the therapeutic benefit. We are doing the exact same thing, but instead of doing it with neurotransmitters, we are doing it with the secreted protein progranulin. The drug blocks the degradation of progranulin, elevates progranulin two to three fold, both in the serum and in the brain. This is what leads to the presumed therapeutic benefit. With our drug, what we have seen is that even after the first injection, you restore progranulin completely to normal level. As long as you give the drug monthly, the high level of progranulin stays. We have patients that have been treated for two to four years, and they have a level of progranulin which is indistinguishable from the level you see in healthy individuals. Okay. You did run a phase II open-label study. It was called INFRONT-2. I just want to discuss the data from the study that gets you and your partner, GSK, excited for the ongoing phase III. We'll start off with the key biomarkers. You did mention progranulin is sort of normalized. What do you see as the most important biomarkers besides progranulin that latozinemab treatment affected and may translate to efficacy? Yeah. So progranulin, again, is the disease-causing protein. Restoring it back to normal levels is no different than enzyme replacement therapies, where you restore the missing enzyme back to normal level. The FDA recognized that and actually elevated progranulin restoration as a core primary in our pivotal phase III. We can discuss this in more detail in a minute. In addition, we view volumetric MRI as a significant biomarker. There is a very strong correlation between brain tissue loss and cognitive decline in frontotemporal dementia. You can measure it with volumetric MRI, both the areas of interest, the frontal cortex and the ventricles, which is a summation of all brain tissue loss. We included volumetric MRI as supportive biomarkers. GFAP is an inflammatory biomarker that's upregulated in multiple types of neurodegeneration, including Alzheimer's disease and frontotemporal dementia. We already showed in phase II that we can normalize it. This is one of the biomarkers that helps [Lacombe] to receive approval. More importantly, most importantly, in the phase II, it was a small open-label study with 12 patients, but we still were able to show, compared to aged and disease-matched controls, we were able to show 48% slowdown in cognitive decline over 12 months. All the data in the phase II, the biomarkers, the imaging, and the clinical readouts really showed the same positive benefit of the drug, which gave us a lot of room for optimism for the phase III. Do levels of GFAP in pre-symptomatic and symptomatic patients sort of correlate with any type of severity of disease or progression or any other clinical outcome? GFAP is normal in pre-symptomatic patients. It elevates in symptomatic patients. We showed, with drug treatment, that we can restore it back to normal level, both in the plasma and in the brain. There is no quantitative correlation between disease severity and the level of GFAP. It just elevates in the disease. Okay. I guess, you know, one investor focus on biomarkers for neurodegenerative and neurodevelopmental disease is neurofilament light chain. Just give us your broad thoughts around this biomarker, but also the observations from the INFRONT-2. light chain (NFL) is an interesting biomarker. It elevates in many, possibly most, neurodegenerative diseases, but it's not always responded to therapy. It responded to therapy very well with tofersen in ALS, and this was the basis for the accelerated approval of tofersen in ALS. For example, neurofilament is elevated in Alzheimer's disease, and it did not go down with the approved anti-ABETA drug. It's not a consistent biomarker for drug response. In our cases, what we saw in our phase II, again, it was a small number of patients over 12 months. We saw what we called stabilization of neurofilament. In frontotemporal dementia (FTD), at least some publications argue that because the disease continued to accelerate, neurofilament keeps going up throughout the time of the disease progression by 20% - 30% every year. We saw at least stabilization over one year. Neurofilament is one of our exploratory biomarkers, but if it's going down, it will help us. If we don't see effect, we don't think it will have any impact on the approval of the drug. Okay. I guess with the lessons learned from INFRONT-2, you moved into phase III, INFRONT-3. It's to read out in, I believe, November or by year-end. Just discuss the overall trial design, including changes to the statistical analysis plan that now incorporates plasma progranulin levels. It's a phase III pivotal study. It's a two-year-long study with 106 symptomatic patients where the sort of approval will be centered on. In addition, we have 16 pre-symptomatic patients that are mutation carriers, but at recruitment did not have symptoms. The core primary clinical readouts are going to be the CDR-Sum of Boxes, which is tailored for FTD. It's an eight-domain cognitive measure that's very similar to Alzheimer's disease. Basically, six out of the eight domains are identical to Alzheimer's disease, plus two additional domains which are tailored to FTD. In addition, the elevation of progranulin in the plasma is the second core primary biomarker. We need to get statistical significance effect in both the clinical readout and in the biomarker to really get clear and clean full approval. As I mentioned, in addition to the core primary, progranulin, and CDR, we are measuring volumetric MRI, GFAP, neurofilament. We are actually going to measure thousands of proteins with proteomics in the plasma and CSF. The main readouts that would support approval are the clinical readouts, the CDR-Sum of Boxes, plus some secondary clinical readouts, progranulin elevation, GFAP, neurofilament, and volumetric MRI. It's a placebo-controlled study. We have internal controls for this study. We recruited both very early patients that have like CDR-Sum of Boxes of 0.5, and 30% of the patients have somewhat more severe clinical symptoms, like a CDR of 2. We really want to see if we can treat patients at every stage of the disease. As I mentioned, we also have pre-symptomatic patients. We want to see if drug treatment can prevent conversion from non-symptomatic to symptomatic. Because so far the drug is very well tolerated with no serious drug-related adverse effects, our ultimate goal is really to do prevention therapy and basically treat patients before they develop clinical symptoms. The 16 patients that we have in the trial, if we see by sensitivity analysis any effect, we will try to get like a broader label that will enable us to treat all FTD with progranulin mutation. What are the powering assumptions on each of the primaries? For the progranulin, based on our phase II studies and all our experience with healthy volunteers and patients, we think that we have more than 99% likelihood of hitting statistical significance. Over the last four years, every individual that was treated with our drug, we saw two to three fold elevation in the level of progranulin. We haven't seen any case of non-responsive patients. We think there is a pretty good likelihood that we will hit this progranulin core primary. For the clinical readout, we have 90% confidence, 80% - 90% confidence that we will show 40% slowdown in cognitive decline. Even if we see 25% slowdown in cognitive decline, it will still be statistically significant according to KOLs that we just recently hosted. Clinically meaningful and in our view will still be approvable. All right. If you have to hit each progranulin as well as the clinical outcome, what's the benefit? Has something changed in terms of? The benefit, again, this is our interpretation, but I think it opens more flexibility or more avenue for possible approval. Our goal is to get full approval with statistically significant cognition and statistically significant progranulin elevation. If in a case where the clinical readouts are trending positively and progranulin is positive, and if we have one or two additional biomarkers, we can still approach the FDA and possibly get approval or at least accelerated approval. If one of the core primaries is possible, we think we may have an avenue to discuss with the FDA. It's a very safe drug from what we can tell. It's a lethal disease that kills people in their prime of life within seven to nine years. There is no approved medication. We think that means there will be a possibility to discuss with the FDA. For the progranulin, you just have to have a difference that's stat-signed. You don't have to normalize or? No, it means that you just have to have stat-signed. Okay. Lastly for this program, just remind us of the GSK deal in terms of economics and rights as well as obligations of each. This drug is a good partnership with GSK. It's a 50-50 profit share in the U.S. Royalties largely resemble a 50-50 profit share ex-U.S. We received $700 million upfront for this deal. There are $1.5 billion of milestones, including $160 million for the first commercial sale in the U.S. and $90 million for the first commercial sales in the EU. We have the commercial leadership in the U.S., so we are starting to get ready for commercialization. We will build a sort of sales force and we are going to lead the commercialization, again, in good partnership with GSK. Ex-U.S., GSK is going to lead the commercialization. They are dependent in a way. They are going to rely on our BLA application and approval, and then they will use it for ex-U.S. The data are expected in early to mid-Q4. If the data are positive, we will apply for a BLA. As I mentioned, we have breakthrough therapy and orphan designation, so we can have, hopefully, an accelerated BLA application. We are getting ready together with GSK for commercialization. Right. I don't know if I misheard you. They will file in the Europe? Yes. Upon approval in the U.S. or? No, that's going to mean we are basically, yes, we are filing. We are filing. We are filing the BLA, and the BLA will be the basis for the EU application. We are doing it together. It means we are not going to wait for approval. Okay. Let's move on and just briefly touch on AL101. Again, another sort of hill in blocking antibody. You did mention that in Alzheimer's disease, you also have a reduction in progranulin. What are the key differences between AL101 and latozinemab? Mechanistically, both of these drugs elevate progranulin by blocking the degradation cascade. There are two independent drugs in the way they bind different epitopes, like different regions on the sortilin degradation receptor. They have different pharmacokinetics. AL101 has a two to three times longer half-life, which enables either less frequent delivery or lower dosing. We think that it will be more applicable for large indications like Alzheimer's disease and Parkinson's disease. As Pete mentioned, we are testing AL101 in early Alzheimer's disease. It's a double-blinded, placebo-controlled study with approximately 360 patients. We are testing two doses of the drug and placebo. It's a 76-week treatment where we will measure cognitive decline in multiple ways, like four different types of cognitive measures, with the primary as a CDR-Sum of Boxes, PET imaging for the misfolded proteins in Alzheimer's disease, ABETA and Tau, and multiple other biomarkers, neurofilament light chain (NFL), GFAP. The scientific rationale for Alzheimer's disease, as I mentioned before, is that even modest reduction in progranulin leads to increased risk of Alzheimer's disease. Progranulin is a formal genetic risk for Alzheimer's disease. Multiple animal model studies done by academic labs show that overproduction of progranulin beyond the normal level is protective in Alzheimer's disease. There are both animal model studies showing that high levels of progranulin are protective and human genetic studies showing that decreased level of progranulin is a risk. That's why we are going after Alzheimer's disease. Is the goal to normalize it or do superphysiological? The goal is to have superphysiological level of progranulin. There are multiple animal model studies, both in Alzheimer's disease, in Parkinson's disease, and in ALS, showing that superphysiological levels of progranulin in the range of 2 - 3 folds are beneficial and are protective in multiple diseases. Where are you in terms of enrollment? Yeah, we completed enrollment in April of this year. It's a 76-week long trial. The trial will be completed in 2026, and we expect data in late 2026, possibly early 2027. Okay. I guess we got a couple of minutes left. We got four minutes or so. Last topic is your brain carrier program. Just briefly touch on it and where you are with that. We have a brain carrier (shuttle) platform, which we are using for multiple drug modalities. We are using it for antibody drugs, including an anti-ABETA drug and a Tau antibody drug. We are using it for enzyme replacement therapies, particularly GBA, which is the enzyme that's mutated. Loss of function in this enzyme causes up to 10% of Parkinson's disease and up to 30% of Lewy body dementia. There are hundreds of thousands of patients in the U.S. and EU that suffer from Parkinson's disease or Lewy body dementia because of GBA mutations. We have engineered GBA with our blood-brain barrier technology that hopefully could repair this pathology. Our third drug modality is siRNA therapeutics that's linked to our blood-brain barrier shuttle. We are focusing on Tau siRNA and alpha-synuclein siRNA. The idea is to be able to inject siRNA peripherally instead of intrathecally directly to the brain and get homogeneous distribution in the brain and basically have much better sort of convenience of use and less safety risks. We think that we have a really good, unique sort of brain carrier (shuttle) technology that could minimize adverse effects and maximize brain penetration. What exactly do these brain carriers leverage in terms of receptors? Yeah, so we are using the transferrin receptor as the carrier. That's, again, something that multiple companies are using, but there are a lot of subtleties in where the brain carrier exactly binds, what's the affinity of this brain carrier. These small differences could really make significant differences in both efficacy and safety. We think that we really optimize the affinity, the epitope, and the different sort of configuration of the transferrin for different drug modalities. We think we have a uniquely flexible, versatile technology, which, again, we should show good brain penetration with minimal adverse effects. Okay, we're running low on time, but you know, if we're sitting here a year from now, what would you like to say are your key achievements? Our key achievements will be an approved drug for frontotemporal dementia with progranulin mutations, with BLA applications that completed data on our phase II study in Alzheimer's disease. Like having two clinical programs that we know the outcome of and at least two, possibly three programs, ABETA drug in Alzheimer's disease, GSK's program in Parkinson's disease, and Tau siRNA, again, in Alzheimer's disease that are either entering the clinic or very close to the clinic. Thank you very much for attending the Alector Healthcare Conference. I look forward to the data later on this year and the progress you’ll make on the rest of the pipeline as well. Thank you very much. Thank you.