Alector, Inc. (ALEC) Earnings Call Transcript & Summary

Good morning, ladies and gentlemen, and welcome to Alector's conference call and webcast highlighting latozinemab and AL101 human monoclonal antibody candidates designed to elevate progranulin levels for the treatment of neurodegenerative diseases. As a reminder, this conference call is being recorded. [Operator Instructions] I would now like to turn the call over to Katie Hogan, Senior Director of Communications and Investor Relations. Please go ahead.

Thank you, operator. Hello, everyone, and welcome to our Progranulin event. Before we begin, I'll go over a few reminders. There will be a moderated question-and-answer session with our management team and speakers following prepared remarks. [Operator Instructions] The webcast replay of this event will be available tomorrow after 12:30 p.m. Eastern Time in the Investors section under Events & Presentations on our website, www.alector.com. I'd like to note that during this call, we'll be making a number of forward-looking statements, and you can find our disclosure right here. Turning now to the agenda. Dr. Sara Kenkare-Mitra, our President and Head of Research and Development, will begin with opening remarks and our perspective on Elevating Progranulin of neurodegenerative disease. Next, Dr. Fenghua Hu, an Associate Professor in the Department of Molecular Biology and Genetics in the Weill Institute for Cell and Molecular Biology at Cornell University will shed light on why Elevating Progranulin holds immense promise for the treatment of frontotemporal dementia and Alzheimer's disease. Following Dr. Hu's remarks, our Vice President of Clinical Development, Dr. Larry Carter will provide a comprehensive overview of our ongoing clinical development efforts around latozinemab and AL101, our human monoclonal antibody candidates. Finally, Dr. Adam Boxer, Endowed Professor in Memory and Aging in the Department of Neurology, Weill Institute of Neuroscience at the University of California, San Francisco will delve into the promising advances in progranulin therapeutic development. With that, I would now like to turn the call over to Dr. Sara Kenkare-Mitra, our President and Head of Research and Development, to make opening remarks. Sara?

Alector was founded a decade ago with the vision that brought together the fields of immunology, human genetics, and neuroscience and pioneered immuno-neurology as a novel therapeutic approach to treat neurodegenerative diseases. Immuno-neurology is conceptually like immuno-oncology. Cancer is now understood as a failure of immune surveillance and instead of targeting cancer cells directly with chemotherapy, with ADCs, biologics and other modalities, we can stimulate and harness the immune system to help eradicate tumors with immuno-oncology treatments. Similarly, a guiding premise of immuno-neurology passes that neurodegeneration is partially or fully the result of the failure of neuroimmune surveillance. In the past few decades, the dominant approach in neurodegenerative disease drug development has centered on targeting misfolded proteins like amyloid beta, tau, alpha-synuclein, TDP-43 and others. While we are pleased to see some recent success with this approach, there is considerable unmet medical need. We believe that our immuno-neurology strategy could complement this existing focus on misfolded proteins and harness the benefits of microglia, the brain's immune system cells to counteract multiple disease pathologies. Microglia routinely performs surveillance of the brain and support neuronal function. Physiologically active microglia surveil for and remove pathogens, cell and protein debris like protein aggregates, dysfunctional nerve cells and damaged synaptic nerve connections. Microglia also migrate towards and have contact with leaky blood vessels to support the integrity of the blood-brain barrier in damaged brain tissue. The capacity of microglia to orchestrate brain health decline -- declines with age due to both the natural senescence process as well as common genetic mutations. And as microglia age, their ability to sustain this surveillance, prevention, support and repair task that are essential for homeostasis in the central nervous system starts to decline. Our approach aims to target this immune dysfunction by seeking to transform these dysfunctional microglia into a healthier disease fighting state. Our clinical pipeline of immuno-neurology programs includes the therapeutic candidates, latozinemab and AL101 that aim to elevate progranulin. Today, we'll shed additional light on latozinemab for the treatment of frontotemporal dementia, or FTD, and AL101 for the treatment of Alzheimer's disease. Both these candidates are being developed in collaboration with our partner, GSK. Alector is also developing AL002, our TREM2 agonist candidate, which is currently in Phase II for the treatment of Alzheimer's disease in collaboration with AbbVie. We recently highlighted this program in a webinar, which was presented last week. While Alzheimer's disease is the most common form of dementia, you may be less familiar with frontotemporal dementia or FTD, a devastating rare form, which is the most common cause of dementia under the age of 60. Sadly, there are no approved treatment options to cure or slow the progression of this disease. People living with FTD can present with compulsive behavior, lack of restraint, apathy, anxiety and aphasia. The condition is frequently misdiagnosed as Alzheimer's disease or depression or Parkinson's disease or even a psychiatric condition. Most people are diagnosed in their 40s and 50s and the life expectancy after diagnosis is around 7 to 10 years. Progranulin encoded by the granulin gene is a secreted glycoprotein, which is primarily expressed in neurons and microglia within the central nervous system and has several activities, including being an immune and neurotropic factor. Progranulin is secreted by activated microglia and promotes neuronal survival, controls microglial function, inflammation and processing of lysosomal enzymes. Progranulin is cleaved by lysosomal proteases into smaller fragments called granulins. Our expert speaker, Dr. Fenghua Hu, will be discussing the current scientific understanding of the role of progranulin in neurodegeneration in detail a bit later. Now mutations in the granulin gene play a crucial role in neurodegenerative disease serving as an either causal factors or increasing the risk of developing these conditions. In neuronal ceroid lipofuscinosis, homozygous loss of function mutations lead to the absence of progranulin. For FTD with granulin gene mutation or FTD-GRN, heterozygous loss of function mutations can result in approximately 50% loss of progranulin, making them a causal factor for FTD-GRN with 90% penetrants by the age of 75. Less severe loss of function mutations are associated with an increased risk of various neurodegenerative diseases, including sporadic FTD, Alzheimer's disease, ALS and Parkinson's disease. Alector was the first company to target progranulin as a treatment approach for FTD-GRN and people living with FTD-GRN represent approximately 5% to 10% of all people with FTD. It is estimated that there are 15,000 symptomatic and 120,000 people at risk with progranulin mutations in the U.S. and Europe. Our commitment extends beyond FTD-GRN as we are actively developing therapies for both FTD-GRN and Alzheimer's disease and our strategic vision involves expanding into other neurodegenerative diseases in the future. Latozinemab for the treatment of FTD-GRN and AL101 for the treatment of Alzheimer's disease are human monoclonal antibodies that was specifically designed to block the interaction of progranulin with one of its trafficking receptors SORT1 or sortilin on the surface of neurons. Our antibodies elevate extracellular progranulin levels by blocking SORT1 and thereby decrease the degradation of progranulin. SORT1 has been identified as a single transmembrane receptor that is believed to play a crucial role in modulating the levels of progranulin. Genome-wide association studies have suggested an inverse correlation between SORT1 expression levels and progranulin levels in humans. Multiple preclinical studies have also demonstrated that the total progranulin levels are elevated following SORT1 ablation. The amount of total progranulin in both the serum and brain tissue lysates of mice lacking sortilin were increased. While SORT1 is known to play a crucial role in regulating progranulin, there is redundancy in the system and progranulin utilizes multiple receptors such as prosaposin, mannose-6-phosphate receptor, LRP1 and others in addition to sortilin for trafficking intracellularly and to the lysosome. The intracellular effects or the essential functions of progranulin do not depend on its transport via SORT1, as noted by evidence that SORT1 ablation in rodents does not result in neurodegeneration. And SORT1 haploid insufficiency is not associated with FTD in humans. Latozinemab and AL101 target distinct regions or binding epitopes on SORT1 protein. With a longer half-life than latozinemab, AL101 potentially offers the flexibility to optimize dosing schedules. While latozinemab is being developed to be a treatment for FTD-GRN, AL101's properties could make it suitable to address a broader spectrum of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Here, we show data on the efficacy of our progranulin elevating antibody in alleviating behavioral effects in aged FTD-GRN mice in a social interaction test. The antibody was dosed at 40 mg per kg once weekly for 4.5 weeks. In the graph on the left, you can see that control-treated granulin mice experienced a notable loss in the majority of matches compared to control IgG treated wild-type mice. In the middle, the Alector Progranulin Elevating Antibody-treated wild-type mice displayed behaviors similar to that of control IgG treated wild-type mice. And on the right, a striking improvement was observed in Alector's progranulin elevating antibody treated granulin mice compared to control IgG treated granulin mice. Overall, our findings highlight that Alector's Progranulin Elevating Antibody successfully reversed behavioral deficits after 4.5 weeks of treatment in aged FTD-GRN mice, underscoring its potential as an effective therapeutic intervention. During preclinical development, we were able to demonstrate the progranulin elevating effects of latozinemab in nonhuman primates. In our 4-week GLP study with nonhuman primates with latozinemab dosed at 200-milligram per kilogram, we observed that latozinemab increases progranulin levels by 2 to threefold in the CSF and serum. Additionally, we also demonstrated that blocking of SORT1 and increases in progranulin in white blood cells upon treatment with latozinemab or AL101, providing proof-of-target engagement. Finally, I want to briefly highlight the clinical development efforts of our progranulin elevating antibodies to date. Latozinemab and AL101 are the most advanced progranulin elevating candidates in clinical development worldwide. Latozinemab is designed to treat FTD-GRN while AL101 is being studied to treat Alzheimer's disease. Later in this webinar, Dr. Larry Carter will be going over our clinical studies and data in detail. Our Phase I trials with latozinemab and AL101 in healthy volunteers demonstrated that latozinemab and AL101 are generally well tolerated and we demonstrated an increased progranulin in plasma and CSF in a dose-dependent manner. We also saw encouraging trends observed across biomarkers of disease activity in our INFRONT-2 Phase II clinical trial. Latozinemab is currently being studied INFRONT-3, a Phase III trial in FTD-GRN participants treated for a duration of 96 weeks. This trial recently achieved target enrollment in October of 2023. AL101 increased progranulin levels in plasma CSF in a dose-dependent manner in a Phase I trial of healthy volunteers. Our partner, GSK, recently commenced patient screening, and we anticipate dosing the first participant with early Alzheimer's disease in the PROGRESS AD study, a Phase II clinical trial of AL101 soon. In addition to our late-stage candidates -- in addition to our late-stage candidates of novel first-in-class immuno-neurology programs, latozinemab, AL101 and AL002, we continue to develop early programs with additional targets currently in preclinical development for the treatment of neurodegenerative disorders like Alzheimer's disease, ALS, Parkinson's and Lewy body dementia. Additionally, we have made significant progress on our proprietary blood-brain barrier technology called Alector Brain Carrier, which we are leveraging across our portfolio to enhance exposure to the CNS. We plan to share more about our early research pipeline and these technologies during a future R&D Day. Our IP portfolio contains 50-plus patent families, which include 73 issued patents and over 500 pending patent applications directed to more than 20 targets and technologies. Our progranulin programs in latozinemab and AL101 are being developed in partnership with GSK. The major partnership includes $700 million in upfront payments and includes a $1.5 billion in development and commercial milestones, a 50-50 U.S. profit share and tier double-digit royalties ex-U.S. Potential milestone payments include $160 million for the first commercial sale in the U.S. and $90 million for the first commercial sale in at least the following countries: France, Germany, Italy, Spain or the U.K. Our substantial global IP portfolio for progranulin includes anti-sortilin compositions, methods of use and treatment, applications in various neurodegenerative diseases, biomarkers and clinical data consisting of issued and pending patents in the U.S. and jurisdictions outside the U.S., reinforcing our commitment to global coverage. With that, I will turn it back over to Katie.

Thank you, Sara. With that back, I'm honored to introduce Dr. Fenghua Hu. Dr. Hu is an Associate Professor in the Department of Molecular Biology and Genetics in the Weill Institute for Cell and Molecular biology at Cornell University. She is a member of the Graduate Fields of Biochemistry; Molecular and Cell biology; Genetics, Genomics and Development; and Biological and Biomedical Sciences. Dr. Hu studies the molecular and cellular mechanisms involved in neurodegeneration, particularly ALS and FTD using a combination of biochemical and cell biological approaches and mouse models. Dr. Hu aims to elucidate cellular and physiological functions of several ALS and FTLD genes, including granulin, C9orf72 and TDP-43. She has authored numerous peer-reviewed research articles on neurodegeneration. At this time, I'd like to turn it over to Dr. Fenghua Hu, to discuss in more detail why progranulin is a promising target for FTD and Alzheimer's disease. Dr. Hu?

Thanks, Katie, for the wonderful introduction, and thanks a lot for including me in this webinar event to discuss my favorite molecule, progranulin and its involvement in Frontotemporal dementia and Alzheimer's disease. So before I start, I just have a brief disclosure -- a few disclosures I have to make according to Cornell's guideline. As you heard from Sara, progranulin encoded by the granulin gene is known as the security glycoprotein comprised of 7.5 granulin repeats. So progranulin has drawn a lot of attention from neuro scientists because its association with frontotemporal dementia. As you heard from Sara, the heterozygous mutation in the progranulin was found to be a leading cause of frontotemporal dementia with a really high penetrants. So this was a discovery made in 2006 by 3 independent groups. Many mutations in the granulin gene were found but do not affect as progranulin have low insufficiency because the mutant allele doesn't -- usually doesn't produce any function protein. So in the patients, they are left about 50% of the progranulin protein. So it interests me, a few years later that homozygous mutations in this case results in total loss of progranulin were found to cause another neurodegenerative disease termed neuronal ceroid lipofuscinosis. So this is actually a class of lysosomal storage disorder. So the main phenotype is accumulation of lipofuscin which is also known as aging pigment, but usually it is caused by dysfunction of the lysosomes. When lysosomes are not functional, then the substrates that target lysosomes for degradation, [indiscernible] from this kind of autofluorescent material. As you can see from this table from a recent review article, so far, there are 14 genes have been found to be mutated in NCL and majority of them include either key lysosome enzyme in case of CLN1 and CLN2 or a key regulator of lysosome function. So progranulin is also known as CLN11. So the assumption was NCL will indicate that progranulin has a really important function in maintaining proper lysosomal activities. So in addition to FTD and NCL, as you have heard already from and Dr. Kenkare-Mitra that in polymorphism in progranulin are also involved in other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. So on the risk allele called AS for polymorphism [indiscernible]. So the risk allele, the [indiscernible] allele located at [indiscernible] of the granulin were found to be associated with lower progranulin levels in -- by several studies, and this risk allele will also shown to be associated with increased risk of Alzheimer's disease and associated with temporal sclerosis and TDP-43 pathology and [indiscernible]. So it seems that loss of function, either total -- I mean, like a progranulin kind of effect neurodegeneration in a dose-dependent manner like either partial loss of function or total loss assumption associated with neurodegeneration. So the question is like how does progranulin prevent neurodegeneration? So during the past, I guess, 17 years, there's a lot of studies done with [indiscernible] mouse models, [indiscernible] derived cells. Also in the human patient samples have indicated that in one key phenotype that caused by progranulin sufficiency is enhanced information. So this includes microglia and astrocyte and misregulated microglia and astrocyte activities often leads to synaptic loss of the neurons and also aggregation of TDP-43 which is DNA binding proteins that is a hallmark of FTD with granulin mutations. So in addition to disinformation phenotype, progranulin is also known as a neurotrophic factor to also promote neuronal survival and recent studies have also shown that progranulin insufficiency in humans will cause disruption of blood brain barrier. So all these effects eventually leads to destruction of brain structure and neurodegenerative dementia seen in human patients. So in the last few slides, I would just like to go through some of these points in more details. So first of all, progranulin is not a key regulator of microglial mediated inflammation. So under progranulin deficiency conditions, microglia are known to [indiscernible] inflammatory cytokines and also complement factors. So complement factors, they contact synapses for elimination. So when you have increased levels of complement factors, often lead to excessive synaptic [indiscernible] circuit defect with neuronal circuit defect in the brain. There is several studies also have shown that in these factors can also trigger lysosomal defects and TDP-43 pathology in the neurons. So in addition to microglia astrocytes also have been shown to play a key role in the pathogenesis because when under progranulin deficiency conditions, they are using IPSC-derived astrocyte or brain amyloid or even in the human patient sample studies have recent -- many several recent reports have shown that astrocyte dysfunction due to progranulin deficiency can drive neuronal phenotypes, including synaptic loss, TDP-43 aggregation and spiking activity changes. In addition to these 2 cell types, a recent study using single-nucleus [indiscernible] of human patient samples, also shown there are several cells that are associated with brain formation, including fibroblast [indiscernible] muscles have been misregulated in the FTD patients with granulin mutations. And in their studies, they also have shown that the interaction between these cells involved in blood brain formation and all the [indiscernible] and astrocytes. So astrocytes also play a critical role in blood brain formation kind of the most disruptive within all the cells or interactions they have analyzed in the human patient samples, suggesting that this could be also one of the key pathology caused by progranulin deficiency of haploid insufficiency. So it seems that we have from the studies in the mass models and human patient samples and then iPSC submodels and other systems that we have seen that the -- we have kind of know the main pathology caused by progranulin deficiency, but then how does progranulin deterioration at molecular and cellular levels. So because of the connection to progranulin and [indiscernible] because progranulin -- total loss of progranulin results in neuronal ceroid lipofuscinosis, which is a lysosomal storage disorder. So one of the key hypothesis is that progranulin deficiency will cause lysosomal dysfunction. And as you [indiscernible] lysosome pathway is one of the key clearance and recycling mechanism in the cell. So lysosomal dysfunction will lead to build up of protein aggregates and dysfunctional organ in the neurons and affecting neuronal health. Lysosomal dysfunction could also lead to dysfunction of the glial cells and then lead to enhanced inflammation and other glial pathology, which could also affect -- result in neurodegenerative phenotypes. Then the question is like how does progranulin regulate lysosome function because when you lose it, do you have the and you will have the -- and the patient will develop an NCL phenotype. So progranulin is really important for proper lysosome function. So from our early studies, we have found that when we stain mouse brain suctions, we found the progranulin is actually [indiscernible] with these 2 lysosomal marker, [indiscernible] indicating that progranulin is the lysosome resident protein, kind of contradictory to the traditional [indiscernible] progranulin and the secretive glycoprotein. So we also figure out the pathways that deliver progranulin to the lysosome. So first of all, progranulin is a protein that synthesize in the secretive pathway. So within the cell, it's synthesized in the endoplasmic reticulum and then when you transport it to the Golgi, it can bind to sortilin as long as its tracking receptor and sortilin can deliver progranulin to the lysosome compartment. There's some residual amount of -- there's some small percentage sortilin on the cell surface of the neurons and that could also mediate the uptake of the progranulin from the extracellular space and deliver to the lysosome compartment. In addition to sortilin, we also found that progranulin can traffic to the lysosome through another sortilin independent pathway, which is mediated by this protein called prosaposin and it's receptor -- mannose-6-phosphate and RP1. So basically, prosaposin can also be secreted, but it also can go to the lysosome through its receptor -- these 2 receptors and prosaposin can give progranulin, kind of piggy back ride to the lysosome in a shortly independent manner. So when progranulin reached to the lysosome, many studies during the past decade have found that this progranulin precursor is processed to this little granulin peptide and the functions still remain elusive, but there's several downstream target being reported, including the lysosomal proteases, cathepsin D, [indiscernible] which is enzyme involved [indiscernible], also the deficiency of progranulin has found to this reduction in lipid species following the [indiscernible] lysosome membrane, this [indiscernible] phosphate. Additionally, we recently found the granulin in peptide combined to lysosome membrane protein, [ CD68 ] in microglia. So clearly, these granulins are probably the functional unit of progranulin in the lysosome, but their function still remain to be fully characterized. So we can -- like from these studies, we can conclude that one important function of progranulin within the cell is help regulate lysosome activities and that could affect the behavior of the neuron and the glial cells. But in addition to this lysosomal pool, it's also known that progranulin, there's a big portion of progranulin being secreted outside the cell. So it's -- and they could also affect the activation and the glial and then neuronal functions. So the extracellular function of the progranulin kind of still remain elusive. But during the past decade of several receptors being identified, including [indiscernible] receptor, FNa2 and a recent study also identified a sortilin [indiscernible] as a progranulin receptor. So we also recently found a secretive phospholipase, which is a key regulator of information as a downstream target of progranulin. So by binding to these receptors are extracellular molecules, progranulin could regulate inflammation response and also on neuronal survival and [indiscernible] events. So kind of to summarize, so we still kind of have a long way to go to fully understand the function of the progranulin, but we kind of know there is two progranulins, one is the intracellular lysosomal progranulin which in the lysosomal progranulin processed to granulin peptide and they are likely to regulate the activity of [indiscernible] lysosome enzymes, but there's also a secretive pool of progranulin that they could potentially regulate inflammation and also neuronal activities through signaling events. So -- and there could be a [indiscernible] between these 2 activities as well, but at this stage, there are a lot of work still need to be done that -- to fully understand how progranulin functions and which pools of progranulin is more important to prevent neurodegeneration. So thank you. I will turn this back to Katie.

Thank you, Dr. Hu. At this time, I'd like to turn it over to Dr. Larry Carter, our Vice President of Clinical Development, to discuss latozinemab and AL101 development efforts. Larry?

Thank you so much, Katie, and hello, everyone. In this section of the presentation, I'll speak to 2 of our Phase II clinical trials, one evaluating the effects of latozinemab and frontotemporal dementia and the second evaluating the effects of AL101 in Alzheimer's disease. So starting with our INFRONT-2 Phase II trial in FTD, this slide shows a schematic of that clinical trial design. It's an open-label study for up to the 96 weeks duration with an optional continuation part of the trial. We've enrolled 3 cohorts in this study. And for the purpose of today, we'll focus on the middle cohort on the slide here, the symptomatic FTD-GRN individuals. In this trial, the primary endpoint and objectives of the study were to evaluate safety and tolerability. However, we had a variety of secondary endpoints and exploratory endpoints to look at PK and PD effects, including some particularly relevant biomarkers and clinical outcome assessments. So starting with the primary objective of the study to characterize safety profile. This slide shows the safety and tolerability across the entire study, but with the FTD-GRN cohort highlighted. And in this trial, we found that the most common adverse events included fall, urinary tract infection, COVID infection, headache and syncope, adverse events that you might expect in this type of patient population. We did not see any treatment-related serious adverse events and only 2 adverse events that led to discontinuation that included the development of ALS and one participant with FTD C9orF72 mutation and the worsening of a pre-existing cardiac condition in one of the FTD-GRN individuals. So overall, I found that latozinemab was quite well tolerated in these participants including in this recent data cut that we presented at CTAD, the most up-to-date characterization of safety in this study. This slide shows a number of key biomarkers and clinical outcome assessments that we focused on in this study. So starting on the left, you can see progranulin as a measure of target engagement, looking for increases in both plasma and CSF. And then you just heard about the importance of lysosomal function and inflammation in frontotemporal dementia. And so we look at a variety of biomarkers, including [indiscernible], complement activation to know that latozinemab is having effect at the level of the lysosome and on inflammation. We're also interested in biomarker such as GTAP and NFL as markers of astrogliosis and axonal damage, respectively. And then volumetric MRI measures as well as a hallmark of the condition that is frontotemporal lobar degeneration. Lastly, we also assess clinical benefit in disease progression using the CDR plus NACC FTLD sum of boxes as an end point. And this is important because it's an endpoint that's been agreed upon with health authorities in terms of supporting regulatory approvals. So starting with the progranulin data. What's shown here are plasma concentrations on the left and CSF concentrations on the right. And you can see that in individuals with FTD-GRN, they're starting at a relative deficit of progranulin concentrations relative to age match controls. This is what we would expect from the literature. However, with latozinemab treatment, we see a relatively rapid increases in plasma and CSF concentrations into a range that is seen in age match controls. Those increases are sustained throughout treatment with latozinemab through the 49 weeks that are shown here. Here in terms of biomarkers of disease activity, we're showing for cathepsin D on the left, LAMP1 in the center panel and C1QB on the right. Comparisons again to age match controls given the open-label nature of the study, the control data are shown in the gray bars. And as you would expect from the literature, we see apparent elevations at baseline in the FTD-GRN individuals across these measures of lysosomal function and inflammation. With treatment of latozinemab here at 6 months and 12 months, we see trends for decreases across each of these backers, potentially indicative of clinical benefit and activity at the level of the lysosome. Similarly for GFAP as a biomarker of astrogliosis as one would expect from the literature, we see elevations relative to asymptomatic individuals in GFAP, both in plasma and CSF. And with latozinemab treatment decreases over time resulting in levels at 49 weeks that are in the range that we see in asymptomatic FTD-GRN carriers. And we're particularly interested in GFAP as a biomarker because there are data in the literature showing associations between longitudinal changes in GFAP and changes in brain atrophy, particularly in temporal loads. Again, characteristic of the condition with degeneration of frontal and temporal volumes. And when we look at that in this study as well, we see encouraging trends across several areas of interest, albeit in a smaller subset of individuals for whom we have this data. But nonetheless, we're encouraged by what appears to be a relative slowing or reduction in the ventricular enlargement we see over time on MRI imaging and also smaller but encouraging trends in a slowing of whole brain atrophy and frontotemporal atrophy of the cortex. Lastly, in terms of the biomarkers, we're also interested in NfL, both in plasma and CSF and here relative to what we see in natural history studies, we see relatively stable levels of NfL in plasma and CSF. Now what's been shown from natural history cohort data is you would expect in symptomatic individuals to see a continued increase in NfL over time, particularly in symptomatic individuals. So this could be indicative of a beneficial treatment effect, although admittedly, it's difficult to interpret without a proper control group. So when we thought about that with regard to analysis of the CDR data, we looked to these same registries, which have been incredibly helpful to support the development and the drug development and FTD. And we went to the GENFI registry in particular, to try and generate a matched control cohort for comparison of the CDR data and this was done in a 3-step process whereby first we looked for all of the individuals, the GRN carriers who had both baseline and post baseline CDR data. We then used a statistical approach of propensity score matching approach using the CDR Sum of Boxes data to match individuals on their baseline level of severity on the CDR Sum of Boxes. And the third step was a blinded clinical adjudication to further refine the matching based on age, gender, baseline plasma NfL levels and FTD disease variant. So each of these 3 steps was done on a completely blinded manner without any knowledge of the progression of the individuals who are being matched and you can see on this slide that there was a control cohort generated of 10 individuals that are relatively well matched to the 12 individuals in the INFRONT-2 trial on aspects such as the CDR Sum of Boxes, age, baseline plasma, NfL levels and disease variant. So when we compare these 2 groups to one another in terms of the disease progression and the trajectory of their CDR scores over time, we see the results on this slide here. So what's plotted is the CDR plus NACC FTLD Sum of Boxes on the Y axis and as you move down that axis, you see increasing Sum of Boxes scores. This is indicative of a worsening of condition over time. And in the gray dash lines, we see individual trajectories in the thinner lines and then the group mean and the thicker dash line. And we see that over a 12-month period, there's an approximate a 6.4 point decrease or worsening on the CDR Sum of boxes in the match control group and a 3.3 point change in the INFRONT-2 cohort. So comparing these 2 groups to one another, we see an approximate 50% slowing of disease progression in the latozinemab-treated individuals relative to the GENFI2 matched cohort. So taken together between the safety profile, biomarker data and the slowing of progression on the CDR Sum of Boxes, these data were encouraging enough to proceed into Phase III clinical development where we are today. And this is a slide that shows the study schematic of the Phase III trial and the extension aspects of that. So as you would expect, the Phase III trial is a randomized, double-blind, placebo-controlled study designed for registration. We're comparing latozinemab at a 60-milligram per kilogram IV dose, to placebo over a 96-week treatment period. Following that period, there is an optional 96-week open-label extension period. For individuals who do not opt into that, they'll have a safety follow-up. And we just recently initiated a continuation study to provide continued access to latozinemab for individuals who complete their participation in the Phase III or the Phase II trials. As Sara mentioned, we are excited to recently complete enrollment in the Phase III trial with over 100 symptomatic FTD-GRN individuals enrolled and 16 at-risk GRN carriers. The primary endpoint in this trial is one that's been agreed upon for regulatory approvals, the CDR plus NACC FTLD Sum of Boxes and then again, we have a number of secondary and exploratory endpoints, including other clinical outcome assessments, the biomarkers that I had mentioned from the Phase II trial, including volumetric MRI. Now changing gears a little bit to AL101 in Alzheimer's disease. This is a slide now showing data from our Phase I study with AL101. This was conducted in 88 healthy volunteers. And it was designed to compare the effects of AL101, given subcutaneously or intravenously relative to placebo. And what's shown on these panels are the increases in progranulin in plasma on the left and CSF on the right. And what you can see is that the intravenous administration of AL101 resulted in robust and sustained increases in progranulin levels, both in plasma and CSF. So this supported taking this forward into Phase II development. And we're also pleased to have recently announced the initiation of screening in this trial. This is the PROGRESS AD study design. This is being led by our co-development partners at GSK and this is a Phase II randomized, double-blind, placebo-controlled trial. It begins with a screening period up to 12 weeks in duration, followed by a 76-week treatment period. We'll be evaluating 2 doses of AL101 or GSK 4527226 relative to placebo. We're enrolling individuals in this trial who have either mild cognitive impairment due to Alzheimer's disease or mild AD dementia and who are amyloid positive. The change from baseline -- or the primary endpoint is the change from baseline on the CDR Sum of Boxes across weeks 52, 64 and 76. And we also have a variety of key secondary endpoints, including the [indiscernible], ADAS-Cog, ADCS, activities of daily living and the ADCOMS, and we'll also be looking at amyloid and tau PET positivity in CSF and plasma. So with that, I'll hand it back to you, Katie, and thank you.

Thank you, Larry. At this time, I'm honored to introduce Dr. Adam Boxer. Dr. Boxer is the Endowed Professor in Memory and Aging in the Department of Neurology Wheel Institute of Neuroscience at the University of California, San Francisco. He directs the neuroscientist clinical research unit in the Alzheimer's disease and frontal temporal degeneration clinical trials program at the UCSF Memory and Aging center. Among other important initiatives, Dr. Boxer has co-chaired the national Alzheimer's Project Act, FTLD Research Committee for the past 4 years, and he was a founding co-chair of the FTLD Research Roundtable. He also co-chairs the PSP research roundtable, an academic industry collaborative group working to speed the development of new therapies for FLTD, CBD and PSP. Today, Dr. Boxer will highlight the promising advances that have been made in Progranulin therapeutic development. Dr. Boxer?

Thanks, Katie, and really a pleasure to be here this morning. These are really exciting times for those of us who are neurologists and treat neurodegenerative disease because we now have disease-modifying drugs that are truly work for Alzheimer's disease, now for SOD1 ALS, and I think soon, hopefully, for Progranulin related FTD. So today, I want to just review -- I think there's a little bit of overlap in what I'll say and what you've heard already today. But I think I want to give you my perspective as a practicing neurologist who's spent my career taking care of FTD in Alzheimer's patients and as well as organizing clinical trials on some number of these issues, including FTD and Progranulin, Progranulin biology. I spent much of my career trying to develop clinical trials for FTD. And so to give you a sense of where we're in and why Alector has achieved an amazing milestone with completion of enrollment of their Phase III program, Progranulin is a therapeutic target and other potential uses of Progranulin and really wanting to emphasize potential roles in Alzheimer's disease. So -- You heard a little bit about GENFI, which is the natural history study that's going on in Europe. In North America, we have now 28 center project. It's funded by the NIH called ALLFTD where we studied both sporadic forms of FTD as well as genetic forms of FTD. And you see that FTD in general, is a rare disease. And Progranulin is one autosomal dominant cause of FTD, but it's even in the FTD space relatively rare. One of the challenges with FTD is there are many different clinical phenotypes, all of this very complicated [men] driven on the left underscores the challenges of developing treatments for this indication because a single pathology may lead to multiple clinical syndromes. And so this operationalized in slide -- sorry, in a figure from a recent paper led by Murray Grossman, who sadly passed away, but he was a leader in the Progranulin research field. And what you see is at the top are different clinical FTD syndromes and these color bars indicate the underlying pathologies. And what you can see is in certain forms of FTD, it's hard to predict the underlying pathology, and that's limited us in doing clinical trials. It looks like my -- good. Okay, clinical trials and sporadic forms of FTD where we can under -- where we can predict the underlying pathology like Semantic Variant PPA, where we know most cases, are TDP Type C or PSP or most cases are for our tau. The other really most active programs are in Progranulin in genetic forms of FTD and that's because we have multiple biomarkers that we can measure, including Progranulin itself. You've heard about neurofilament MRI, potentially [indiscernible] and other fluid biomarkers that may be useful for clinical development. You've heard quite a bit about Progranulin biology and discovery. I won't go through this in great detail, but just to say, again, there is an example of a brain image of someone who has advanced Progranulin disease, a lot of atrophy, out of white matter disease. Many different clinical syndromes caused by Progranulin mutations, but by far the most common, our behavioral varying FTD and progressive non-fluent aphasia. There are multiple mutations, which cause FTD -- due to Progranulin. And one of the challenges, unlike autosomal Alzheimer's disease is that we can't predict someone's age of onset based on their familial or parental age of onset. And this has been some challenge in designing clinical trials. These are data from about 2 years ago from the all FTD network just showing the prevalence of different related family members from Progranulin as well as other FTD causing mutation carriers as well as the prevalence of sporadic or de novo cases that we discover a Progranulin disease. And what you can see is that Progranulin even in the setting of autosomal dominant, FTD is a relatively uncommon cause, but important therapeutically as you've seen already. You've seen this figure again one of the advantages of developing therapies for Progranulin-related diseases. We can measure Progranulin levels in plasma or CSF and show that they are really low in progranulin mutation carriers but normal in other forms of FTD and controls. Somehow this, we don't know exactly why this leads to a neuropathology called FTLD Type A, which involves deposition of insoluble protein called TDP-43 and in the cytoplasm. We now -- there's another protein that comes along with it, often called TMEM106B, which is very interesting because -- it turns out that TMEM106B is also implicated in normal aging and is an intrinsic lysosomal protein. And when you have a certain polymorphism in the TMEM106B gene, it actually protects a small number of people who have this rare polymorphism from Progranulin related diseases. It also turns out that the same polymorphism protects people from unhealthy brain aging and also from limbic predominant age-associated TDP-43 encephalopathy, which is a common co-pathology in Alzheimer's disease. So somehow these low programming levels lead to lysosomal dysfunction you heard a lot about that already today and also possibly this lysosomal dysfunction leads to other problems, including inflammation and synaptic loss, which lead to the clinical syndrome that we recognize as frontotemporal dementia. Increasingly, there's been a lot of detailed studies of the biology of the lysosome and how loss of Progranulin affects us. You heard quite a bit about this already. I'll just say of the advantages and why this is ever more promising for developing Progranulin therapies is now we can look at specific lipid molecules that are associated with the lysosome and use them as pharmacodynamic endpoints in clinical trials Also, increasingly, as we recognize that there's this other protein, TMEM106B which is intrinsically present in the lysosome, we can measure this and investigate its role in conjunction with Progranulin loss in TDP-43 in different neurogenerative diseases. So this is an important co-factor that we can study. People have been doing clinical trials in FTD for many years. The first truly positive clinical trial in FTD. I think I lost the references here in my slides, but was from over 20 years ago with trazodone and this showed that the antidepressant helped with behavior. We did the first industry-sponsored large clinical trial in North America of memantine over 10 years ago, probably 15 years ago now and showed that it had very transient benefits in FTD, but ultimately after 6 months really wasn't associated with the benefit. So there's a lot of experience with doing clinical trials, particularly of a symptomatic agents in FTD but the advantage of focusing on Progranulin as we know exactly what neuropathology we're targeting, and we have a pretty good understanding of the underlying mechanism. So about 15 years ago, there was an organization called Consortium for FTD Research that was funded by a family -- who a large family who knew that they had a Progranulin mutation running in the family and through that, a basic science effort, a high throughput screen initially identified histone deacetylase inhibitor SAHA as something that could -- in an animal model -- excuse me, in a cell culture model, could raise Progranulin levels. And so this really was the first idea to that was picked up by industry to develop clinical therapeutics for FTD Progranulin. There was a company called InVivo Therapeutic that developed a small molecule to raise Progranulin levels with also an HDAC inhibitor. And in parallel with that effort, there were multiple academic efforts to look at commonly available drugs that were also identified through high-throughput screens as raising Progranulin. Finally, the InVivo started their trial -- go back there, in 2015, and I'll show you the results. So one of the first trials that was done in Progranulin was done by our group at CSF. This was with nimodipine. Nimodipine was shown in a transgenic mouse model to raise Progranulin levels. What we saw is that it had no effect on raising Progranulin either in plasma or in CSF, and you can see that these are controls, these are Progranulin mutation carriers. And really, there was -- unfortunately, nimodipine didn't work. So we knew how to do a negative trial. But one of the interesting things is we showed that we could measure longitudinal brain atrophy and also that certain biomarkers in CSF, including neurofilament light, but also interesting A-beta 42 and tau seemed to be associated with the severity in Progranulin, which is interesting now as we think more about using these therapies Alzheimer's disease. This was the first industry-sponsored clinical trial done by [indiscernible] Pharmaceuticals of a blood-brain barrier permeable HDAC inhibitor. Unfortunately, we never achieved high enough plasma or CSF levels to actually affect Progranulin concentrations. And so this was also a negative trial. But one of the nice things about this trial is we were able to include FDG PET and show that FDG PET as how strongly correlated with clinical and other biomarker measures, and it's another endpoint potentially usable in clinical trials for Progranulin therapeutics. You've seen this slide about 3x already today, but I just want to underscore from my perspective as a clinical trial, all the excitement about actually having a positive clinical trial that showed elevation of Progranulin from a treatment. And I think this was really exciting and unprecedented after 15 years of work. And so really exciting to see what clinical effects latozinemab will have in our patients. Since the first Progranulin therapy trial efforts, we've done a lot of work to in our natural history studies, both on all FTD and in GENFI through a global organization now called the FTD Prevention Initiative, where we can show that we can take data from different FTD mutation carriers and develop basin disease progression models and you can see that these models are highly predictive of disease progression. On the x-axis is the estimated year of disease where zero is the onset of symptoms. And you can see that data from 2 completely independent mutation carrier cohorts are totally superimposable. So for GENFI in blue, and in light blue and ALLFLD in dark blue. And this is, again, the CDR-NACC-FTLD Sum of Boxes that you heard about from Larry, and you can see this very sharp increase in this end point, which is being used in the Phase III around the time of symptom onset. We also see that in different types of FTD causing mutations, you have different rises in endpoints and different end points that are best to capture disease progression. But importantly, green is Progranulin here in the combined population, and this has the most aggressive form of FTD and the most rapid form of disease progression, and we can look to see how -- what the optimal clinical endpoints are in a clinical trial. And we can see that for different FDA mutation carriers, still the primary end point, the best endpoint to capture clinical disease change is what's being used in the Alector trial of CDR-NACC-FTLD Sum of Boxes. But importantly, in Progranulin mutation carriers, you can see in purple here, that neurofilament levels in the plasma go up long before the onset of symptoms. We can start to detect a deviation in controls at about 10 years prior to onset of symptoms in some individuals. And then MRI also -- this is a frontal lobe region of interest prior to the onset of symptoms. And importantly, this suggests that if the latozinemab is effective in the current Phase III, it might be possible to do a prevention trial where we initiate treatment or before the onset of symptoms and prevent FTD, which is really the goal of much of our work in the FTD prevention initiative. So really exciting eagerly awaiting the Phase III results of the Alector study. I want to switch now to Alzheimer's disease because I also lead a number of Alzheimer's disease clinical trial programs and see a lot of patients with this. And I think that increasing recognition in the Alzheimer's disease field that despite all the excitement around the approval of anti-amyloid therapy with aducanumab and hopefully soon donanemab it may be a little bit more complicated to see really significant efficacy in most patients with Alzheimer's disease because most patients do not have pure amyloid and tau but have a multi proteinopathy with TDP-43 being the second most common co-pathology. And I think very few people maybe 10% of late onset Alzheimer's disease is actually pure A-beta and tau. And so increasingly, we have to think about combination therapy approaches where we may wish to combine an amyloid and maybe a drug that acts on TDP-43 for treatment of sporadic Alzheimer's disease. And interestingly, you heard a lot from Fenghua already, but there's quite of evidence of Progranulin is involved actually Alzheimer's pathology. So this is from the Tom Beach's group. And you can see that in individuals with early or brain regions with early Alzheimer's pathology, a lot of Neuritic plaques, these Neuritic plaques are really coated Progranulin, suggesting that Progranulin in a human Alzheimer's brain, maybe regulating inflammation, maybe trying to tamp down that in some way. By the time you have significant tau pathology, the amount of Progranulin goes down, suggesting that maybe in that -- by that it's too late to limit Progranulin. So one of the interesting things that I like to think about is that in Alzheimer's disease, these are all the different changes in biomarkers we can measure with amyloid and soluble amyloid and insoluble amyloid as well as soluble tau, insoluble tau biomarkers. But really, again, just like you saw with FTD, there's this rapid increase in symptoms around the onset of inside tau deposition, which is really -- see a tipping point, somehow something's happening here that with the deposition of insoluble proteins that's leading to the onset of symptoms. And so one thing that I like to think about what be causing this a lot and interestingly, we think about beta amyloid, the amyloid that's associated with neurodegeneration. But it turns out that many neurodegenerative proteins actually form an amyloidogenic component that is deposited in neurodegenerative diseases. So the typical Alzheimer's disease we think is A-beta amyloid and tau, both tau can also form an amyloid that has a specific structure in Alzheimer's disease. And we, again, see that often this is accompanied by TDP-43. For Progranulin, which is TDP type-A usually, we see TDP-43 and TMEM106B. And so the question is, why are all of these proteins may be accumulating together? And again, you've heard that maybe it has something to do with lysosomal dysfunction or proteostatic dysfunction due to alterations are lowering or insufficient Progranulin. So I think this is a promising approach to be trying in Alzheimer's. There's also a lot of evidence that's been around for years. This has worked from Keith Josephs and the Mayo Group looking retrospectively at patients in Alzheimer's disease. And then in autopsy were found to have TDP-43 co-pathology. And what you can see is that it's been understood quite some time the TDP-43 that accumulates in Alzheimer's disease as a co-pathology really probably increases the rate of disease progression and rate of brain atrophy. So this is really an important target as we think about trying to develop more -- more effective Alzheimer's therapies. This is a nice paper from my colleague, Keith Johnson at Harvard from the Harvard aging brain study hot off the press, just came out neurology. And again, when they -- in the Harvard aging brain study, they're not looking at patients who have manifest or symptomatic Alzheimer's disease, they're looking at people who are particularly normal and are technically thought to be normal aging and what they found is that about 10% of these patients start to decline cognitively even in the absence of an Alzheimer's disease diagnosis probably have are expected to have TDP-43 or late related cognitive decline. So this -- with this little red area of the pie is also probably related to TDP-43. And again, the major protective factor for this is a TMEM106B protective allele which is the same thing that protects against prevailing Progranulin related disease. So even in normal aging, it may be that raising Progranulin levels could also affect the onset of cognitive symptoms. So with that, I just want to conclude that it's really exciting to see all the rapid progress in understanding Progranulin biology and disease. We've heard a lot about the biology from other experts today. I won't go through it again. But really in FTD, we believe that a Progranulin related neurodegeneration is probably the low-hanging fruit for therapeutics and that this is going to be the first cure possibly for dementia. And while previous clinical trials were challenging to complete, you've seen that Alector really deserves a great lot of credit in completing enrollment for their Phase III program, and they have multiple biomarkers. They can measure to look at the effects of this drug as well as clinical end points. And we're really excited not only about the potential for elevating Progranulin in FTD, but also in other [indiscernible], particularly for myself since I will see a lot of these patients, with alzheimer's disease. So with that, I just want to thank the many funders that have said my work and my colleagues in the all FTD and GENFI research networks. So with that, thanks very much, and I will pass along to the next spear.

Great. Thank you, Adam, and thanks to all our speakers today. So to summarize -- to summarize, Alector has pioneered immuno-neurology and latozinemab and AL101 are our 2 drug candidates that are currently being developed for the treatment of FTD-GRN and AD, respectively. We believe targeting SORT1 to increase Progranulin has therapeutic potential and latozinemab is the most advanced candidate being evaluated in a pivotal Phase III study for the treatment of Frontotemporal Dementia with a granulin mutation. Our path forward with the Progranulin candidates is marked by exciting milestones and opportunities. For latozinemab, as we said in October of 2023, we achieved target enrollment of 103 symptomatic and 16 at risk FTD-GRN participants in our pivotal INFRONT-3, Phase III trial for a treatment duration of 96 weeks. And for AL101, our partner GSK anticipates dosing the first participant in the Progress AD Phase II clinical trial for early Alzheimer's disease soon. Our strategic vision includes expansion into additional indications such as ALS, Parkinson's disease and other neurodegenerative diseases. At this time, we'll open the lines for questions.

And our first question is going to come from the line of Pete Stavropoulos with Cantor Fitzgerald.

Thank you for hosting this presentation. Very informative. I have a couple of questions for Dr. Boxer. Can you touch on how the primary endpoint for INFRONT-3, the CDR, Sum of the Boxes for FTD performs as a clinical measure in the population enrolled in INFRONT-3, including the other stage of disease and the other genetic group? And what would you consider a clinically meaningful difference between active arm and placebo?

So I don't have the data from INFRONT-3, but I can tell you from the natural history studies. Those curves that I showed, which really represent 300 Progranulin mutation carriers data that you see very -- so the INFRONT-3 study is enrolling people who are symptomatic. So their CDR Sum of Boxes is 0.5 or greater, I believe, which is really on the up slope of the curve. So it's really rising very quickly in those individuals, and you expect to see really rapid change. So that's why it's such a great endpoint. The endpoint was initially developed by Dave Notman, about 15 years ago as part of a natural history study. He put together for a sporadic dating. In terms of clinically meaningful changes, hard to know. I think I would accept personally a 25% to 30% reduction in the rate of progression the FTLD-CDR Sum of Boxes. But I think we'd have to really look at the data and what we've learned from other neurodegenerative programs recently and I point to to first and as an important example is that this is a relatively short observation period you may only see a relatively small effect size during a clinical trial, but this may translate now as we see longer-term treatment data with tofersen, which is another genetically determined neurodegenerative disease in ALS that after a couple of years of exposure, this translates into huge clinical benefits. So and I think -- we have to take a look at the date, but if there are significant effects on the end points, I think we would all be incredibly enthusiastic about that.

All right. And just one follow-up. So there are known genetic modifiers about familial FTD and specifically for FTD-GRN. How prevalent are they? And what I'm trying to understand is whether the genetic modifiers are prevalent enough that you will take them into consideration when designing a clinical study? Perhaps do a prespecified subgroup analysis or just make there's a balance in various arms?

So -- great question. So I don't know exactly the details of what Alector is doing. But for the -- by far, the strongest genetic mode is that TMEM106B allele. And most people who have that, which is actually very, very rare even within the setting of Progranulin mutation carriers, there's very few of these individuals. But we probably never even find them because they never develop symptoms. And so they would not have even been eligible by virtue of the enrollment criteria of the INFRONT-3 study for enrollment. So the other genetic modifiers have very small effects, if any. We can't -- we're not even sure about the effects on disease progression in our models. So yes, I don't think that that's going to play a big role.

Yes. I'll perhaps make a few comments just in terms of the INFRONT-3 enrollment. So first, with regard to the CDR and global scores, we're doing individuals. I mentioned, we have 16 at-risk carriers and then also for symptomatic individuals with global scores ranging from 0.5 to 2. I should note that we've capped the maximum number of participants enrolled with the CDR global score of 2, so the most severe individuals. So this is to say, one, we have a pretty large range of severity in the trial. And the bulk of those individuals are going to be individuals with global scores of 0.5 or 1 at base one. So consistent with the idea that it's likely better to treat earlier in the disease course. We have the majority of participants with that severity of baslines. So I think I'm optimistic about -- we'll learn a lot across the individuals with different stages of severity. With regard to some types or I should say, the potential protective alleles as Dr. Boxer mentioned, say, the prevalent of TMEM106B is relatively rare. So we haven't proactively excluded those individuals. But of course, we'll be interested post-hoc and looking at subgroup and if we have individuals there, whether there's a relatively different effect size compared to individuals who are not carriers of that protective allele.

And our next question is going to come from the line of Jeff Hung with Morgan Stanley.

In INFRONT-2, there was restoration of Progranulin which slows annual disease progression, but doesn't stop it. Is there a specific threshold of brain tissue loss and cognitive decline where stopping disease progression is no longer a realistic goal? And could that be achieved if a patient is treated earlier? And then I have a follow-up.

Dr. Boxer, do you want to start there and maybe we can add on the Alector side?

Sure. Yes. I mean I think -- well, -- we don't really know, honestly with brain atrophy, what -- how that translates to clinical symptoms. Clearly, treating earlier is better. I think that there's -- from other neurodegenerative diseases, that seems to be the case, and I would expect they would apply to this drug as well. But I think in the INFRONT-3 study, people will -- most people will be relatively mild. So it's likely that they will benefit. And I think there's plenty of room to measure treatment effect. Again, looking at the clinical development of other therapeutics like tofersen or lecanemab, what the successful programs have done the same thing here with latozinemab is to start in a symptomatic population and then to measure a treatment effect on a clinical endpoint in the symptomatic population and then to go earlier. It's very, very risky to start in a presymptomatic population. But you'll see, again, in those other initiatives that, that's been the successful path. And that's the same path being taken here.

Just to add to what Adam said, like it's very possible that as the duration of the treatment increase, the magnitude of the effect will increase, as we mentioned for tofersen and actually also for anti-beta therapeutics, means, i.e., join an allergy to a braking distance even if you press the break on the disease, it takes some time for the brain to heal and for the -- and for the clinical symptoms to slow down and hopefully eventually stop, but it's possible that the magnitude of the effect is really will be dependent on the duration of the treatment. So even though in our open label Phase II, we see -- sort of approximately 50% slowdown, which is very profound already. It's possible that with a longer treatment effect duration we will see even stronger effect.

Great. And can you talk about your plans with the data from the presymptomatic patients in INFRONT-3 and how that might be used either in your current or future element plans?

Yes, I can comment on that. Again, drawing attention back to -- we've enrolled 16 individuals in that trial. I think we benefit from the overall duration that we have, both in the placebo-controlled portion, but then the 96-week open label extension in addition to the 5 individuals that we have in the Phase II trial. So I think that will be a meaningful data set from those individuals, not likely to be adequately powered for statistical inferences. But I think we'll learn a lot the longitudinal changes that we'll see over time. And Dr. Boxer alluded to the sort of prodromal changes that we see across several biomarkers. So we're as eager to see the data in the at-risk carriers as we are in the symptomatic individuals and hopefully build the case that we're having a beneficial effect in those individuals as well.

And our next question is going to come from the line of Paul Matteis with Stifel.

This is Kathryn on for Paul. So on the INFRONT-3 program and the new step plan where you can move forward with the smaller sample size, are you still powered for a 40% effect size? And if so, what are the assumptions that underlie this? And what gives you confidence here?

Yes. So with the changes we made to the statistical analysis, we're not compromising power at all. So the study is still power a 40% effect size and can detect an effect size even lower then that down to 25%. So the change in the overall sample size is actually not that different from the way the study was originally designed because we've enrolled mostly symptomatic individuals in the trial. So with that 90 out of 200 symptomatic individuals, the trial is still equitly powered as it was originally designed.

Our next question comes from the line of Yaron Werber with TD Cowen.

This is Brendan on for Yaron. Maybe just 1 quick 1 for the [indiscernible], and I think 1 for the team. So I guess for both the doctors, if you're seeing kind of realistically, if you think about 48% disease slowing, the Progranulin levels that Alector is getting now. Would you expect, based on everything you know and all the information you presented, would you expect to see higher clinical efficacy with higher Progranulin expression? And I guess we're kind of trying to understand how high you can feasibly go before you run into potential issues? And I have a question for the team.

I guess I can start. I mean I think we really do -- that's a great question. We don't understand or I don't maybe to what our team does what the relationship with super normal Progranulin levels and clinical benefit might be or other effects. So I think at least restoring levels to normal or in the normal range or at least a little bit above the normal range seems to be, I think, just to first approximation sufficient. I think there's plenty of evidence that at least in short-term studies, raising Progranulin to very high levels or super normal levels. It doesn't -- it's not associated with any harm. There is a theoretical risk of of protein cancer because as you probably know, Progranulin has also been independently identified breast cancer, some breast cancer cases as something that allows the tumor to avoid probably immune surveillance. So that's a theoretical risk. I'm not sure that it's ever been seen actually with treatment. So hard -- that's about as much -- that's a limit of my knowledge, I'll say. I'll let the Alector team.

Or Dr. Hu, anything you want to add before we chime in?

Yes. So Progranulin -- increased Progranulin expansion has been correlated with a lot of cancer progression tumorigenesis. So there is a risk there, but I really don't know what is the range. Now how much can be tolerated. But I would think restoring into a number range will be very beneficial.

I was just going to draw folks attend back to when we presented the safety results from the Phase II trial, the most recent data cut and we recently presented those data at CTAD for the C9 cohort. That's a cohort of individuals who are starting from Progranulin levels that are similar to what you see in healthy volunteers. And not only do we see in that cohort that reliable 2 to threefold increase in Progranulin levels. But because they're starting from that level in healthy volunteers, we are elevating Progranulin levels to super physiological levels in those individuals. And thus far, albeit the numbers are relatively small. We don't see a marked a markedly different safety profile in the C9 cohort relative to the GRN cohort. That said, I think one of the attractive features of the mechanism of action of latozinemab and blocking sortilin that we're relying on that endogenous production and elevation of Progranulin. So there may be a bit of a ceiling effect at that 2 to threefold elevation that could be a beneficial feature.

Yes, if you draw an analogy, it's not necessarily the [indiscernible] analogy. But if you draw an analogy to SSRI, which elevates the level of [indiscernible] serotonin or norepinephrine like twofold elevation is beneficial, but if you over elevate, you start seeing adverse effects. So we may -- again, we don't know that, it's all theoretical, but we may be in like the [Progranulin] level of restoring or along exactly to normal level and in some cases, a little bit above, but I think that excessive level of Progranulin may have theoretical risk.

And then just one quick one, if I could. Just trying to understand AL101 here. If the INFRONT-3 study is positive with latozinemab, I mean, would you consider testing 101 in FTD-GRN? Or is that really going to be exclusively focused on some of these larger indications? And I really just trying to get at the kind of the magnitude of difference in the profile is hearing if you think it would warrant kind of another FTD study with 101 afterwards.

Yes. I mean probably -- yes, as Sara spoke to, these are really differentiated molecules, and we don't have plans to evaluate AL101 in frontotemporal dementia.

And our next question is going to come from the line of Corinne Jenkins with Goldman Sachs.

Maybe 1 for Dr. Hu. I noticed that in your description of the mechanism, Progranulin. And one of the things you highlighted was the [indiscernible] place in delivering Progranulin to the lysosomal as kind of a core active about protein function with respect to lysosomal dysfunction. So how does inhibiting sortilin 1 as proposed by these 2 molecules impact particular pathway reactivation?

That's a great question. So I think if you inhibit sortilin line from our study from shorting [indiscernible] mice, you will get a decreased lysosomal Progranulin and EPS level of granulin peptides. And at the same time, you get elevated levels of furans progranulin, both in [indiscernible]. So as kind of I -- in my last slide, mentioning just these 2 [indiscernible] we really don't know which pool is more important in preventing neurodegeneration. Some of our recent studies suggest that maybe the actual cellular Progranulin could enhance lysosomal function as well. So -- and I guess the data from the Alector's clinical trial would suggest that there may be decreasing the levels of granulin peptide by anti-sortilin antibody therapy and boosting the level of [indiscernible] might be beneficial at the [indiscernible] stage dementia patients.

Okay. And maybe like a reverse the question that was just asked, which is that given the level of differentiation between the 2 molecules to the extent 001 didn't demonstrate enough efficacy an FTD would you consider pursuing it with 101? Thing there could be a better profile there.

That's not -- I don't really know how to answer this question.

It's possible we could explore that, Corinne. That's not our current focus. The focus on 101 is really positioned for the larger indications. And it does have a longer half-life. I think as Larry mentioned, we feel we're well powered. Even at a lower level of clinical progression slowing with the 001 study. But it's possible we could consider that. That's not the current plan.

And our next question comes from the line of Graig Suvannavejh idea with Mizuho Securities.

So I've got several. Maybe the first for Dr. Hu, we are aware that there are multiple Progranulin-based candidates in development across a variety of indications. And so I was wondering if you could just maybe provide a high-level perspective, do you think pluses and minuses are each of the candidates and kind of the indications that they're going after and how 001 might be the ideal approach? And then my next questions are for Dr. Boxer with respect to INFRONT-3 in expectations. I was just wondering on the safety side, wondering if you could provide your thoughts on what you would think would be acceptable safety and tolerability, especially vis-a-vis potential ARIA? And then also your thoughts on biomarkers that are being collected and which of the biomarkers in your mind, are most important for us to pay attention?

Got a lot in there, Graig. We'll start with the first part for and Dr. Hu. I think the question is just how we're looking at the different Progranulin elevated approaches out there.

Yes, I think overall, because growing insufficiency is driving cost for FTD. So if you can boost Progranulin function or levels will be beneficial. So it's a really hard question. I feel like as we kind of discussed earlier, we don't know what is the range that Progranulin can be beneficial. And we you have too much than you can risk of driving cancer progression. So maybe I think with the [indiscernible] approach is mainly playing [indiscernible] Progranulin. So I mean [indiscernible], so it won't go super high. Other approaches with molecules, I'm not really familiar with these clinical channels or the AV Progranulin. So I'm not sure whether it would be the range of Progranulin elevation they are looking at. And I guess, my kind of main kind of concern will be really the Progranulin level and overall level and maybe it's also distribution. Maybe Dr. Boxer can better answer this question because I think you might know the other clinical trials better than I do.

Sure. Yes. I mean I think there -- I mean that I'm aware of, there are 4 other clinical trial programs underway in the Progranulin space, 3 of them are AAV Progranulin programs. One is a recombinant Progranulin that has a brain [indiscernible] link to it. Hard to know what will be most successful. I think in my mind, one of the advantages of a drug approach as opposed to a gene therapy approach is that you can adjust the dose if you get to -- if it turns out that a super normal programming level is not safe or is not ideal. You can reduce the dose, and it will still be fine. With AAV gene therapy, there's a good turn that once you do it. If it's effective, you can't turn it off and you can't adjust you have no control over what happens. So I think that's the concern in my mind before AAV right now, even though one has done is attractive in other ways. But safety-wise, I think this is probably the safest approach. In terms of biomarkers -- so in terms of safety and INFRONT-3, I don't really have any priority concerns about the safety. I mean there haven't any safety signals to date, but I know of that meaningful. In terms of biomarker effects, well, the ones that we're very interested in are neurofilament but you saw which is not an ideal biomarker in fluid because it's a very long half-life. GFAP has a shorter half-life and therefore, and maybe a little bit more specific to Progranulin effects on the astrocytes in the brain. And so that may be even better. But neurofilament, GFAP, brain atrophy would be enforced very exciting if they saw a change there. Other downstream biomarkers of lysosomal function. But ultimately, as a Phase III program, I think you have to see a clinical effect as you move forward.

And our next question is going to come from the line of Tom Shrader with BTIG.

Thank you, and thank you for another terrific presentation. I wanted to return to Dr. Hu. A little bit with the idea whether the Progranulin is doing what you would want it to do. Does the rate of change of things like lysosomal function and GFAP makes sense if you had corrected things because the extracellular Progranulin levels normalize very quickly? Does the rate of change of everything else give you confidence, make you wonder -- just how do you see those data? And I have a follow-up for Dr. Boxer.

Yes. I think [indiscernible] because I think from the cell [indiscernible] review sortilin is a receptor attracting receptor for Progranulin that taking Progranulin from the Golgi or actual cellular space to the lysosome compartment. So when you block this trafficking, you end up with lower decreased lysosomal Progranulin and also the level of granulin peptides and then with the company an increase in the full and Progranulin levels, which could be found in the [indiscernible] space. But I think now the field, it is -- I think we don't know the exact function of the granulin peptide in the lysosome. Even reports slaiming some of the granulin peptide could be toxic compared to [indiscernible] Progranulin really between Progranulin and granulin peptide, I mean the full lens versus the small peptides. I think I just need more study to figure out that exact function. The actual cellular programming is kind of in the past before the association to Frontotemporal Dementia was found Progranulin is known as a growth factor in something like a growth factor manner to drive information and tumor genesis, it promotes cell perforation. So this actual cellular Progranulin pool, it could have many functions that we have not kind of explored yet and I felt like the data from Alector kind of suggest that maybe this pool Progranulin might be more important than the [indiscernible] of granulin peptide in at least in this treating patients with severe neurodegenerative phenotype rarity.

Okay. I was just going to comment. I mean, I think we're really encouraged by the changes that we've seen on the [indiscernible] lysosomal function, inflammation,astrogliosis. There's still a lot that's not known in terms of you would expect in terms of the temporal dynamics, I think, in part because we haven't seen these types of changes before. So we're really encouraged by what we're seeing so far.

And then for Dr. Boxer, you've treated a huge number of these patients, how noisy is the primary endpoint in untreated patients over the course of the study if a patient was flat, is that very definitive in your mind? Or do patients bounce around? And how tricky is training people to use this rating scale? Is it straightforward where the cytocide variability is low or is it complicated?

Well, again, most of the people are really progressing very rapidly by the time enrolled in a study like INFRONT-3. So yes, I mean, if someone didn't progress at all over the 96-week trial, that would be huge. As you'd expect really prominent changes over that time and I know that the CDR Sum of Boxes is a very common endpoint in Alzheimer's disease trials and has been used in Aducanumab, Anetumab every other recent trial. And so operates really well in very large international multicenter trials. And so the FTLD-CDR Sum of Boxes just adds 2 other domains not really substantially different and all the same training and reliability issues that have been not issues, but to see good training and reliability that's been demonstrated in Alzheimer's trials applies I think also to a program like this.

And I can comment perhaps just strictly from a clinical trial perspective, there's a number of things that we employ to try and reduce the noise, whether it be radar training, centralized review of the scoring of the CDR. So there's a number of aspects that we employed to reduce that inter-site variability and even Intra-rater reliability, keeping the same readers at the sites to the extent possible. So there's a lot of things we employ from a clinical trials perspective to reduce any noise in the system.

Our next question is going to come from the line of Myles Minter with William Blair & Company.

You've got Sara on for Myles. R&D I've got a couple [indiscernible] Similar to the protective [indiscernible] changes, are there any evidence of [indiscernible] function mutations in [indiscernible] or other positives of endogenous elevations of Progranulin like a SORT1 block of function mutation that you guys have seen? And if so, are those mutations protective? I'm less concerned about like enrollment in a trial, but more from a mechanistic point of view.

Yes. I don't know, Dr. Hu. Do you want to start on that? Maybe we can add from the Alector side if you have experience there?

Is the question about TMEM106B, whether it's [indiscernible] allele. Sorry, I didn't get -- can you repeat your question maybe.

Yes, sorry. So I'm just curious is there any gain of function in the patients in like GRN or loss of function mutations in SORT1 that leads to [indiscernible] increases in Progranulin? And if those are protective similar to what we see with the [indiscernible]?

No, I'm not aware of any gain of function in mutations in Progranulin.

Again, the relations between sortilin and Progranulin was identified through genetic polymorphism. There are small -- there are polymorphism that changed the level of Progranulin. There are rare people that have heterozygous, a function of sortilin, but they are the number of people that carry this genetic mutation is too small to really derive any conclusions regarding protection.

I'm going to ask log off. Are there any last questions for me?

I believe we have 1 additional question in the queue. Dr. Boxer, but thank you for your time. If you have to log off. We can cover it.

I can answer one quick question.

Sarah, did you have a follow-up for Dr. Boxer?

Not for Dr. Boxer, but I do have 2 for the Alector team at their time.

Okay. We can hang on for those. Maybe operator, go to our last person on the line and then we can let Dr. Boxer go.

Great. So just then following up on kind of the theoretical risk of cancer we've discussed with high levels of Progranulin. Just to clarify, is this something that the Alector team has observed in-house in the clinical studies? And is this something you guys are monitoring in the Phase III study?

It's certainly something that we're monitoring in the Phase III study. Links back to kind of the strength of the mechanism of action and elevating levels to within a range seen in healthy controls. So it would be logical to think that if you're in that range that you're observing in healthy volunteers that you're not resulting in an elevated risk of cancer. But certainly, the longitudinal clinical data that we'll have at the end of day will be telling for that. It's certainly something that we're interested in. We're monitoring and don't have any signals we're on to date.

Yes, no preclinical signals either. There's no safety signal related to oncogenesis in our program whatsoever.

Great. And then 1 more quick 1 for me. Are there any NFL threshold requirements in the symptomatic patients INFRONT-3? Or is that something you guys are just looking at in the presymptomatic patients?

Yes, only in the presymptomatic patients. So no NFL requirements for eligibility in the symptomatic individuals.

Thank you, Sarah. And operator, I think we have time for one more.

Our last question will come from the line of Neena Bitritto-Garg with Deutsche Bank.

So I just wanted to ask a kind of theoretical question about just to read through from some of the biomarker data that you've seen to date to the impact on TDP-43. And the reason I ask is just to kind of understand how we could potentially read the FTD-GRN INFRONT-3 data to potential in Alzheimer's and other diseases where there is a TDP-43 component?

Yes. Thanks, Neena. Too late we lost Dr. Boxer there, I'm sure you should have helped there with perspective. It's great to have you back. I don't know Dr. Hu, If you have any comments there, if Arnon, others want to comment.

Not really. I mean I know TDP-43 is kind of found in both FTLD and it's pretty common for AD as well. But yes, sorry, I don't have any knowledge about the clinical side.

Arnon and Gary, if you want to add more.

I mean, in general, if we see efficacy in one indication, it will suggest that the drug is is effective. It's sort of elevating for Progranulin to the right level. It's elevating Progranulin in the right place. It elevates Progranulin without blocking its function. So I think the overall efficacy in any clinical indications will increase the general probability of success in other indications, but we still have to do clinical trial in each indication to show efficacy.

This is Gary Romano. Yes. But especially in the in the TDP-43 indications, if you know that in FTD granular, it's -- we do have -- it's TDP-43 pathology. That's really why our interest in ALS, in C9 and even in Alzheimer's disease or [indiscernible]. So we're eagerly waiting for biomarkers of TDP-43 so that we can assess that. I think that's coming pretty soon, hopefully. But -- yes, but definitely a positive result in this Phase III study would increase the interest of us and our colleagues at GSK.

Okay. Thank you, Neena, and thanks, everyone.

Thank you. This concludes today's conference call. Thank you for participating, and you may all disconnect.