Good morning, ladies and gentlemen, and welcome to Alector conference call and webcast highlighting latozinemab and AL101, its human monoclonal antibody candidates designed to elevate progranulin levels for the treatment of neurodegenerative diseases. As a reminder, this conference call is being recorded. Currently, all participants are in a listen-only mode. There will be a question and answer session at the end of this call. To ask a question over the phone during this session, you will need to press star one one on your telephone. You will then hear an automated message advising you your hand is raised. To withdraw your question, please press star one one again. I would now like to turn the call over to Katie Hogan, Senior Director of Corporate 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. To submit a written question, please type it into the question and answer panel on the webcast. The webcast replay of this event will be available tomorrow after 12:30 P.M. Eastern Time in the investor section under Events and Presentations on our website, www.allector.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 for the treatment of neurodegenerative disease. Next, Dr.
Fenghua Hu, an Associate Professor in the Department of Molecular Biology and Genetics and 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 a 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 posits that neurodegeneration is partially or fully the result of the failure of neuroimmune surveillance. In the past two 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's considerable unmet medical need.
We believe that our immunoneurology 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 perform 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. As microglia age, their ability to sustain the surveillance, prevention, support, and repair tasks 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 2 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 forties and fifties, and the life expectancy after diagnosis is around 7-10 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 neurotrophic 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 lipofuscinoses, 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% penetrance 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. People living with FTD-GRN represent approximately 5%-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.
Lecanemab, for the treatment of FTD-GRN, and AL101 for the treatment of Alzheimer's disease, are human monoclonal antibodies that were 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 was 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 haploinsufficiency is not associated with FTD in humans. Lecanemab and AL101 target distinct regions or binding epitopes on the SORT1 protein... With a longer half-life than Lecanemab, AL101 potentially offers the flexibility to optimize dosing schedules.
While lecanemab 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 four and a half 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 behavior similar to that of control IgG-treated wild-type mice. 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 non-human primates. In our 4-week GLP study with non-human primates with latozinemab dosed at 200 milligrams per kilogram, we observed that latozinemab increases progranulin levels by 2- to 3-fold 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 1 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 2 clinical trial. Latozinemab is currently being studied in INFRONT-3, our phase 3 trial in FTD-GRN participants treated for a duration of 96 weeks. This trial recently achieved target enrollment in October 2023.
AL101 increased progranulin levels in plasma and CSF in a dose-dependent manner in a phase 1 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 2 clinical trial of AL101 soon. In addition to our late-stage candidates of novel first-in-class immuno-neurology programs, lecanemab, 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+ patent families, which includes 73 issued patents and over 500 pending patent applications, directed to more than 20 targets and technologies. Our progranulin programs, 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 tiered double-digit royalties ex-US. Potential milestone payments include $160 million for the first commercial sale in the US and $90 million for the first commercial sale in at least two of the following countries: France, Germany, Italy, Spain, or the UK.
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, Sarah. With that background, I'm honored to introduce Dr. Fenghua Hu. Dr. Hu is an associate professor in the Department of Molecular Biology and Genetics and 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?
Hi, and 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. So as you heard from, Sara, that, progranulin, encoded by the granulin gene, is known as a secreted glycoprotein comprised of 7.5 granulin repeats. So progranulin have drawn a lot of attention from neuroscientists because, its association with frontotemporal dementia. As you heard from, Sara, that heterozygous mutation in the progranulin was found to be a leading cause, of frontotemporal dementia, with a really high penetrance.
So this was a discovery made in 2006 by three independent groups. Many mutations in the granulin gene were found, but the net effect is progranulin haploinsufficiency, because the mutant allele doesn't usually produce any functional protein. So in the patients, they are left about 50% of the progranulin protein. So interestingly, 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 the accumulation of lipofuscin, which is also known as aging pigment, but usually is caused by dysfunction of the lysosomes.
When lysosomes are non-functional, then the substrates that target to lysosome for degradation can get crossing and form this kind of autofluorescent material. As you can see from this table, from a recent review article, that there are so far 14 genes have been found to be mutated in NCL, and main majority of them encode either a key lysosome enzyme, in the case of CLN1 and CLN2, or a key regulator of lysosome function. So progranulin is also known as CLN11. So the association with 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 Dr.
Sara Kenkare-Mitra, that, you know, polymorphisms in progranulin are also involved in other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The risk allele called rs4848, a polymorphism. So the risk allele, the T/T allele, located at 3' UTR of the granulin, were found to be associated with lower progranulin levels by several studies, and this risk allele were also shown to be associated with increased risk of late-onset Alzheimer's disease, and associated with subcortical sclerosis and TDP-43 pathology, Braak stage, and tau pathology.
So it seems that, in loss of function, either total I mean, you know, like a progranulin kind of affect neurodegeneration in a dose-dependent manner, you know, like partial, either partial loss of function or total loss of function, and it's associated with neurodegeneration. So the question is, like, how does progranulin prevent neurodegeneration? So during the past, I guess, 17 years, there, there's a lot of studies done, with, knockout mouse models, also iPSC-derived cells. Also, you know, human patient samples have indicated that, you know, one key phenotype that, caused by progranulin insufficiency is enhanced inflammation.
So this includes microglia and astrocyte, and the misregulated microglia and astrocyte activities often leads to synaptic loss of the neurons and also aggregation of TDP-43, which is a RNA and DNA binding proteins that is a hallmark of FTD with granulin mutations. So, in addition to the this inflammation phenotype, progranulin is also known as a neurotrophic factor, so also promote neuronal survival. And a recent studies have also shown that progranulin insufficiency in humans will cause disrupt the blood-brain barrier. So all these effects eventually leads to destruction, destruction of brain structure and neuro neurodegenerative dementia seen in human patients. So in the last few left slides, I would just like to go through some of these points a little more details.
So first of all, progranulin is known a key regulator of microglia-mediated inflammation. So under progranulin deficiency conditions, microglia are known to upregulate pro-inflammatory cytokines and also complement factors. So complement factors, they can tag synapses for elimination. So when you have increased levels of complement factors, often lead to excessive synaptic pruning and circuit defect with neuronal circuit defect in the brain. Several studies also have shown that, you know, these factors can also trigger lysosomal defect and TDP-43 pathology in the neurons.
So in addition to to microglia, astrocyte also have been shown to play a key role in the pathogenesis because when under progranulin deficiency conditions, they're using iPSC-derived astrocyte or or brain organoid or even in the human patient sample studies have several recent reports have shown that astrocyte dysfunction due to progranulin deficiency can drive neuronal phenotypes, including synapse loss, TDP-43 aggregation, and spiking activity changes. In addition to these two cell types, a recent study using single-nucleus RNA-seq of human patient samples also shown that several cells that associate with blood-brain barrier formation, including fibroblast, mural cells, endothelial cells, pericytes, and smooth muscles have been misregulated in the FTD patients with granulin mutations.
In their studies, they also have shown that the interaction between these cells involved in blood-brain barrier formation and also the interaction between these cells and astrocyte. So astrocyte is also play critical role in blood-brain barrier formation kind of the most disrupted within, you know, all the cell-cell interactions they have analyzed in the human patient samples, suggesting that, you know, one of the this could be also one of the key pathology caused by progranulin deficiency or haploinsufficiency. So it seems that, you know, we have you know, like, from these studies in the mouse models and the human patient samples, and then, you know, iPSC cell models and other systems that, you know, we have seen that, you know, we have kind of know the main pathology caused by progranulin deficiency.
But then how does progranulin prevent neurodegeneration at molecular and cellular levels? So because of the connection to progranulin to NCL, 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 might know already, the lysosome pathway is one of the key clearance and a recycling mechanism in the cell. So lysosomal dysfunction will lead to build up of protein aggregates and dysfunctional organelle in the neurons and affecting neuronal health. Lysosomal dysfunction could also lead to dysfunction of the glial cells, and then leads to, you know, enhanced inflammation and other glial pathology, which could also affect, you know, lead to result in neurodegenerative phenotypes.
Then the question is like, how does progranulin regulate lysosome function? Because when you lose it, you know, you have, and the patient will develop NCL phenotype. You know, so, clearly, progranulin is really important for proper lysosomal function. So from our early studies, we have found that, you know, when we stain the mouse brain sections, we found the progranulin is actually colocalized with these two lysosomal marker. Number one, cathepsin D, indicating that progranulin is a lysosome resident protein, kind of contradictory to the traditional view of progranulin as a secreted glycoprotein. So we also figure out the pathways that deliver progranulin to the lysosome. So first of all, progranulin is a protein that's synthesized in the secretory pathway.
So within the cell, it's synthesized in the endoplasmic reticulum, and then when it's transported to the Golgi, it can bind to sortilin as one its trafficking receptor, and the sortilin can deliver progranulin to the lysosome compartment. There's some small percentage of sortilin on the cell surface of the neurons, and that could also mediate the uptake of the progranulin from the extracellular space and deliver it 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 its receptor, mannose-6-phosphate receptor, M6PR. So basically, prosaposin can also be secreted, but it also can go to the lysosome through its receptor, these two receptors.
Prosaposin can give progranulin, kind of piggyback right to the lysosome in a sortilin-independent manner. So when progranulin reach to the lysosome, many studies during the past decade have found that this progranulin precursor is processed to these little granulin peptide, and the functions still remain elusive. But there are several downstream target being reported, including the lysosomal protease, cathepsin D, the glucocerebrosidase , which is enzyme involved in converting glucosylceramide to ceramide. Also, the deficiency of progranulin has found to lead to a reduction in lipid species found in the endosome lysosome membrane, this monoacylphosph glycerol phosphate. Additionally, we recently found a granulin E peptide can bind to a lysosome membrane protein CD68 in microglia.
So, so clearly, you know, these granulins are probably the functional unit of progranulin in the lysosome, but their function, you know, still remain to be fully characterized. So, so we can like from these studies, we can conclude that, you know, one important function of progranulin within the cell is how, you know, regulate lysosomal activities, and that could, 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 out of cell. So it's, And they could also affect, you know, the activation and the, the glial and the neuronal functions.
So, the extracellular function of the progranulin kind of still remain elusive, but during the past decade, there are several receptors being identified, including Notch, TNF, five receptor, ephrin A2, and a recent study also identify a sortilin homolog, called SORCS2 as a progranulin receptor. So, we also recently found a secreted phospholipase, which is a key regulator of inflammation as a downstream target of progranulin. So by binding to these receptors or extracellular molecules, progranulin could regulate inflammation response and also neuronal survival and then signaling events. So kind of to summarize, you know, 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's two pool progranulin.
One is the intracellular lysosomal pool progranulin, and which in the lysosome, progranulin is processed through granulin peptide, and they are likely to regulate the activity of a set of lysosome enzymes. But there's also a secreted pool of progranulin that they could potentially regulate inflammation and also neuronal activities through signaling events. So, and there could be a crosstalk between these two activities as well, but you know, that we are at this stage that you know, a lot of work still need to be done to fully understand how progranulin functions and which pools of progranulin is more important to prevent neurodegeneration. So thank you. I will hand 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 lecanemab and AL101 development efforts. Larry?
Thank you so much, Katie, and hello, everyone. In this section of the presentation, I'll speak to two of our phase 2 clinical trials. One, evaluating the effects of lecanemab in frontotemporal dementia, and the second, evaluating the effects of AL101 in Alzheimer's disease. So starting with our INFRONT-2 phase 2 trial in FTD, this slide shows a schematic of that clinical trial design. It's an open-label study for up to 96 weeks duration with an optional continuation part of the trial. We've enrolled 3 cohorts in this study, and for the purposes 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 the safety profile, this slide shows the safety and tolerability across the entire study, but with the FTD-GRN cohort highlighted. 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 two adverse events that led to discontinuation. That included the development of ALS in one participant with FTD C9orf72 mutation, and the worsening of a pre-existing cardiac condition in one of the FTD-GRN individuals.
So overall, found that latozinemab was quite well-tolerated in these participants, including in this recent data cut for 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 cathepsin D and LAMP1, complement activation, to know that latozinemab is having effect at the level of the lysosome and on inflammation.
We're also interested in biomarkers such as GFAP 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 and disease progression using the CDR plus NACC FTLD Sum of Boxes as an endpoint. 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-matched controls. This is what we would expect from the literature.
However, with aducanumab treatment, we see relatively rapid increases in plasma and CSF concentrations into a range that is seen in age-matched controls. Those increases are sustained throughout treatment with aducanumab 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-matched controls, given the open label nature of this 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 aducanumab, here at 6 months and 12 months, we see trends for decreases across each of these biomarkers, 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 aducanumab 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 lobes. Again, characteristic of the condition, with degeneration of frontal and temporal volumes.
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. 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. 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 in FTD. And we went to the GENFI registry in particular, to try and generate a matched control cohort for comparison of the CDR data.
This was done in a three-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, a 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. 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. Each of these three steps was done in a completely blinded manner, without any knowledge of the progression of the individuals who were 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 two 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 dashed lines, we see individual trajectories in the thinner lines, and then the group mean in the thicker dashed line. And we see that over a 12-month period, there's an approximate 6.4-point decrease, or worsening on the CDR sum of boxes in the matched control group, and a 3.3-point change in the INFRONT 2 cohort. So comparing these two groups to one another, we see an approximate 50% slowing of disease progression in the latozinemab treated individuals, relative to the GenFI 2 matched cohort. So taken together between the safety profile, the biomarker data, and the slowing of progression on the CDR sum of boxes, these data were encouraging enough to proceed into phase 3 clinical development, where we are today.
This is a slide that shows the study schematic of the phase 3 trial and the extension aspects of that. As you would expect, the phase 3 trial is a randomized, double-blind, placebo-controlled study designed for registration. We're comparing latozinemab at a 60 mg/kg 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 3 or the phase 2 trials. As Sara mentioned, we're excited to recently complete enrollment in the phase 3 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. 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 2 trial including volumetric MRI. Now, changing gears a little bit to AL101 and Alzheimer's disease. This is a slide now showing data from our phase 1 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. What's shown on these panels are the increases in progranulin in plasma on the left and CSF on the right.
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 2 development. 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. This is a phase 2 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 two doses of AL101 or GSK4527226, 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 IADRS, iDICOG, 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 very much.
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, Weill Institute of Neuroscience at the University of California, San Francisco. He directs the Neurosciences Clinical Research Unit and the Alzheimer's Disease and Frontotemporal Degeneration, excuse me, 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 four 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 FTLD, 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 wanna 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 and Alzheimer's patients, and well, as well as organizing clinical trials on some number of these issues, including FTD and progranulin, progranulin biology.
I've spent much of my career trying to develop clinical trials for FTD, and so give you a sense of where we've been and why Alector has achieved an amazing milestone with completion of enrollment of their phase 3 program, progranulin as 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 a now 28-center project that's funded by the NIH called ALL FTD, where we study 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 a 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 Venn diagram on the left underscores the challenges of developing treatments for this indication, because a single underlying pathology may lead to multiple clinical syndromes. And so this is operationalized in a slide, in a figure from a recent paper led by Murray Grossman, who sadly passed away, but who was a leader in the progranulin research field. And what you see is at the top are different clinical FTLD syndromes, and these color bars indicate the underlying pathologies.
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 in sporadic forms of FTD, where we can predict the underlying pathology, like semantic variant PPA, where we know most cases are TDP type C or PSP, where most cases are 4R tau. The other really most active programs are in progranulin and 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 FDG-PET, 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's an example of a brain image of someone who has advanced progranulin disease, a lot of atrophy, a lot of white matter disease. This many different clinical syndromes caused by progranulin mutations, but by far the most common are behavioral variant FTD and progressive nonfluent aphasia. There are multiple mutations which cause FTD due to progranulin. 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 two 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 of 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're really low in progranulin mutation carriers, but normal in other forms of FTD and controls.
Somehow, we don't know exactly why, this leads to a neuropathology called FTLD type A, which involves deposition of insoluble protein called TDP-43 in the cytoplasm. We now know 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 disease. 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 I'll come back to, but which is a common co-pathology in Alzheimer's disease. So somehow, these low progranulin levels lead to lysosomal dysfunction.
You heard a lot about that already today. 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 this. You heard quite a bit about this already. I'll just say one 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 and TDP-43 in different neurodegenerative diseases. So this is an important cofactor 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, done with trazodone, and this showed that this 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 symptomatic agents in FTD, but the advantage of focusing on progranulin is 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 the Consortium for FTD Research that was funded by a family, a large family who knew that they had a progranulin mutation running in the family.
Through that, a basic science effort, a high-throughput screen initially identified a 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 that was picked up by industry to develop clinical therapeutics for FTD progranulin. There was a company called EnVivo Therapeutics that developed a small molecule to raise progranulin levels, was 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 EnVivo started their trial. Oop, let me go back there.
In 2015, I'll show you the results. So one of the first trials that was done in progranulin was done by our group at UCSF. This was with nimodipine, and 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.
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, Aβ42 and tau, seemed to be associated with disease severity in progranulin, which is interesting now as we think more about using these therapies in Alzheimer's disease. This was the first industry-sponsored clinical trial done by Forum 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 is strongly correlated with clinical and other biomarker measures, and is another endpoint potentially usable in clinical trials for progranulin therapeutics. You've seen this slide about three times already today, but I just wanna 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 lecanemab will have in our patients.
Since the first progranulin therapeutic trial efforts, we've done a lot of work to in our natural history studies, both in 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 Bayesian 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 0 is the onset of symptoms. And you can see that data from two completely independent mutation carrier cohorts are totally superimposable. So for GenFI in blue and in light blue, and in all FTD in dark blue, and this is again, the C9orf72 CDR, NACC, FTLD sum of boxes that you heard about from Larry.
You can see this very sharp increase in this endpoint, which is being used in the phase 3 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 endpoints that are best to capture disease progression. But importantly, green is progranulin here in the combined and in the combined population, and this has the most aggressive form of FTD and the most rapid form of disease progression. We can look to see what the optimal clinical endpoints are in a clinical trial. We can see that if for different FTD mutation carriers, still the primary endpoint, the best endpoint to capture clinical disease change, is what's being used in the Alector trial, the C9orf72 CDR plus 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 symptoms from 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, you know, if the lecanemab is effective in the current phase 3, it might be possible to do a prevention trial where we initiate treatment 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 3 results of the Alector study.
I wanna 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 there's an increasing recognition in the Alzheimer's disease field that despite all the excitement around the approval of anti-amyloid therapy lecanemab, 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 Hu already, but there's quite a bit of evidence that progranulin is involved in 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 with progranulin, suggesting that progranulin in a human Alzheimer's brain may be regulating inflammation, may be 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, you know, by that point, it's too late to limit the progranulin. So you know, 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 and insoluble tau biomarkers. But really, again, just like you saw with FTD, there's this rapid increase in symptoms around the onset of insoluble tau deposition, which is really a tipping point. Somehow something's happening here that's with the deposition of insoluble proteins, that's leading to the onset of symptoms.
And so, you know, one thing that I like to think about, what might be causing this a lot? And interestingly, we think about beta amyloid as 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, all the typical Alzheimer's disease we think of is beta amyloid and tau. But 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, or, the question is, why are all of these proteins maybe accumulating together?
Again, you've heard that maybe it has something to do with lysosomal dysfunction or proteostatic dysfunction due to alterations, or lowering, or insufficient progranulin. So I think this is a really promising approach to be trying in Alzheimer's disease. There's also a lot of evidence that's been around for years. This is work from Keith Josephs and the Mayo group, looking retrospectively at patients who had 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 for quite some time that the TDP-43 that accumulates in Alzheimer's disease as a co-pathology really probably increases the rate of disease progression and the rate of brain atrophy. So this is really an important target as we think about trying to develop 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 in 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 clinically normal and are technically thought to be normal aging. And what they found is that about 10% of these patients who start to decline cognitively, even in the absence of an Alzheimer's disease diagnosis, probably have, are suspected 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 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. You've heard a lot about the biology from other experts today. I won't go through it again. But really, in FTD, we've believed that a progranulin related neurodegeneration is probably the low-hanging fruit for therapeutics, and that this is gonna be the first cure, possibly for dementia.
While previous clinical trials were challenging to complete, you've seen that Alector really deserves a great deal of credit in completing enrollment for their phase 3 program, and they have multiple biomarkers they can measure to look at the effects of this drug, as well as good clinical endpoints. We're really excited not only about the potential for elevating progranulin in FTD, but also in other multiproteinopathies, 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 supported my work and are my colleagues in the ALLFTD and GenFI Research Networks. So with that, thanks very much, and I will pass along to the next speaker.
Great. Thank you, Adam, and thanks to all our speakers today. To summarize. To summarize, Alector has pioneered immuno-neurology, and latozinemab and AL101 are our two 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 3 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 symptomatics and 16 at-risk FTD-GRN participants in our pivotal INFRONT-3 phase 3 trial for a treatment duration of 96 weeks.
For AL101, our partner, GSK, anticipates dosing the first participant in the PROGRESS-AD phase 2 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.
Thank you. As a reminder, as a reminder, to ask a phone question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile our Q&A roster. Our first question is going to come from the line of Pete Stavropoulos with Cantor Fitzgerald. Your line is open. Please go ahead.
Hi. Thank you for hosting this presentation. Very informative. I have a couple questions for Dr. Boxer. You know, can you touch on how the primary endpoint for INFRONT-3, the CDR, some of the boxes for FTD, performs as a clinical measure in the population enrolled in INFRONT-3, including the 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, you know, 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 upslope 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 Knopman about 15 years ago as part of a natural history study he put together for sporadic AD. In terms of clinically meaningful changes, hard to know.
I think, I would accept personally, you know, a 25%-30% reduction in the rate of progression on the FTLD CDR sum of boxes. But I think we'd have to really look at the data. And, you know, what we've learned from other neurodegenerative programs recently, and I point to tofersen as an important example, is that, you know, 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.
Again, I think we have to take a look at the data, but if there are significant effects on the endpoints, I think we would all be incredibly enthusiastic about that.
All right. Thank you for that. And just one follow-up, you know. So, you know, there are known genetic modifiers of a familial FTD, and specifically for FTD-GRN. You know, how prevalent are they? And, you know, what I'm trying to understand is, you know, whether the genetic modifiers, you know, are prevalent enough that, you know, you would take them into consideration, you know, when designing a clinical study. You know, perhaps do a pre-specified subgroup analysis or just making sure that there's a balance in various arms. So are we-
Yeah, great question. So, I don't know exactly the details of what Alector is doing, but, you know, for the by far the strongest genetic modifier 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 if there are true effects on disease progression in our models. So, yeah, I don't think that that's gonna play a big role.
Okay, thank you. I'll hop into the queue again.
Yeah, and I'll perhaps make a few comments just in terms of the INFRONT-3 enrollment. So first, with regard to the CDR global scores, we're enrolling individuals. You know, 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 a 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 baseline. 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 at baseline. So I think we're optimistic about what we'll learn a lot across the individuals with different, at different stages of severity. With regard to the subtypes, or I should say, the potential protective alleles, you know, as Dr. Boxer mentioned, the prevalence of TMEM106B is relatively rare. So we haven't proactively excluded those individuals, but of course, we'll be interested post-hoc in looking at subgroups 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.
Thank you, and one moment for our next question. Our next question is gonna come from the line of Jeff Hung with Morgan Stanley. Your line is open. Please go ahead.
Thanks for taking my questions. 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. Yeah, I mean, well, we don't really know, honestly, with brain atrophy, what that how that translates to clinical symptoms. Clearly, treating earlier is better. I think there's, you know, 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, you know, in the INFRONT 3 study, most people will be relatively mild, so it's likely that they will benefit, and I think there's plenty of room to measure a treatment effect.
You know, again, looking at the clinical development of other therapeutics, like tofersen or lecanemab, you know, what the successful programs have done is same thing here with donanemab, 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 pre-symptomatic population. But you'll see again in those other indications 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 sort of duration of the treatment increase, the magnitude of the effect will increase. As he mentioned, for tofersen and actually also for anti-beta therapeutics, I mean, I draw an analogy to a braking distance. Even if you press the brake on the disease, it takes some time for the brain to heal 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 the open-label phase II, we see 50, sort of approximately 50% slowdown, which is very profound already, it's possible with the
that with a longer treatment effect duration, we will see even stronger effect.
Great, thanks. And can you talk about your plans with the data from the pre-symptomatic patients in INFRONT-3, and how that might be used either in your current or future development plans? Thanks.
Yeah, 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'll 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 with the longitudinal changes that we'll see over time. And Dr. Boxer alluded to, you know, 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.
Thank you.
Thank you, and one moment as we move on to our next question. Our next question is gonna come from the line of Paul Matteis with Stifel. Your line is open. Please go ahead.
Hi, this is Catherine on for Paul. Thanks for taking our question. So on the INFRONT-3 program and the new stats 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? Thank you.
Yeah, so with the changes we made to the statistical analysis, we're not compromising power at all. So the study is still powered for a 40% effect size and can detect an effect size even lower than that, down to, you know, 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 90-100 symptomatic individuals, the trial is still adequately powered as it was originally designed.
Thank you.
Thank you, and one moment as we move on to our next question. Our next question comes from the line of Yaron Werber with TD Cowen. Your line is open. Please go ahead.
Hi, guys. This is Brendan on for Yaron. Thanks very much for taking the questions. Maybe just one quick one for the KOLs and I think one for the team. So I guess, for both the doctors, if you're seeing kind of realistically, if you're seeing about 48% disease slowing, with 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 think 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 don't. That's a great question. We don't understand, or at least I don't, maybe the Alector team does, what the relationship with supernormal progranulin levels and clinical you know benefit might be or other effects. So, you know, I think at least restoring the levels to normal or in the normal range, or at least a little bit above the normal range, seems to be you know, I think just a first approximation sufficient? I think there's plenty of evidence that, at least in short-term studies, raising progranulin to very high levels or supernormal levels is not associated with any harm.
There is a theoretical risk of promoting cancer because, as you probably know, progranulin has also been independently identified in breast cancer, some breast cancer cases, as a 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, you know, that's about as much as, t hat's the limit of my knowledge, I'll say. I'll let the Alector team weigh in.
Or Dr. Hu, anything you want to add before we chime in?
Yes, I can. Yes, sir.
You may be on mute.
You hear me? Oh, okay.
Yeah, we hear you.
Yeah, so, yeah. So increased progranulin expression 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, you know, the range now how much can be tolerated. But I would think, you know, restoring it to a normal range will be very beneficial.
Yeah, but perhaps-
Yes. Go ahead.
I was just gonna draw folks' attention back to, you know, when we presented the safety results from the phase 2 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, you know, not only do we see in that cohort that reliable 2- to 3-fold increase in progranulin levels, but because they're starting from that level in healthy volunteers, you know, we are elevating progranulin levels to super physiological levels in those individuals. And thus far, you know, albeit the numbers are relatively small, we don't see 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 lecanemab and blocking sortilin is 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 3-fold elevation, and that could be a beneficial feature.
Yes, if you draw analogy, it's not necessarily the right analogy, but if you draw analogy to SSRI, which elevates the level of neurotransmitters, of serotonin or norepinephrine, like two, twofold elevation is beneficial, but if you over-elevate, you start seeing adverse effects. So we, we may a gain, we don't know that it's all theoretical, but we may be in, like, the Goldilocks level of restoring progranulin exactly to, to normal level, and, and in some cases, a little bit above. But I think that excessive level of progranulin may have theoretical risk.
Okay, got it. That's super helpful. Thanks very much. And then just one quick one, if I could. Just trying to understand AL101 here. If the INFRONT-3 study is positive with lecanemab, I mean, would you consider testing AL101 in FTD-GRN, or is that really gonna be exclusively focused on some of these larger indications? And, and I guess really just trying to get at, the kind of the magnitude of difference in the profiles here, and if you think it would warrant kind of another FTD study with AL101 afterwards.
Yeah, I mean, so currently, yeah, as Sarah spoke to, and, you know, these are really differentiated molecules, and we don't have plans to evaluate AL101 in frontotemporal dementia.
All right. Great. Thanks very much, you guys.
Thanks, Brendan.
Thank you. One moment while we get to our next question. Our next question is gonna come from the line of Corinne Jenkins with Goldman Sachs. Your line is open. Please go ahead.
Thanks, and good afternoon. Maybe one for Dr. Hu. I noticed that in your description of the mechanism of progranulin, one of the things you highlighted was the role sortilin plays in delivering progranulin to the lysosome as kind of a core aspect of that protein's function with respect to lysosomal dysfunction. So how does inhibiting sortilin one, as proposed by these two molecules, impact that particular pathway reactivation?
That's a great question. So I think if you inhibit sortilin from our study, from sortilin knockout mice, you will get a decreased lysosomal pool of progranulin and a decreased level of granulin peptides. At the same time, you'll get elevated levels of full-length progranulin, both intracellularly and extracellularly. So as kind of I, in my last slide, mentioned, you know, there's these two pools of progranulin, and right now, I feel like, we really don't know which pool is more important in preventing neurodegeneration. Some of our recent studies suggest that, you know, maybe the extracellular pool progranulin might could enhance lysosomal function as well.
I guess the data from the Alector's clinical trial would suggest that there may be, you know, decreasing the levels of granulin peptide by anti-sortilin antibody therapy, you know, and then boosting the level of full-length progranulin might be beneficial at the, you know, late-stage dementia patients.
Okay, thank you. And maybe, like, a reverse of the question that was just asked, which is that, you know, given the level of differentiation between the two molecules, to the extent 001 doesn't demonstrate enough efficacy in FTD, would you consider pursuing it with 101, thinking there could be a better profile there?
You mean, that's not, I don't really know how to answer this question. Maybe Dominic-
That can be fair with the company broadly?
Yeah.
Yeah.
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, you know, 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.
Okay, thank you.
Yep.
Thank you, and one moment as we move on to our next question. Our next question comes from the line of Graig Suvannavejh with Mizuho Securities. Your line is open. Please go ahead.
Thanks so much. Thanks for doing the presentation, and thanks for taking my questions. So I've got several. Maybe the first for Dr. Hu. You know, 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 on what you think the pluses and minuses are each of the candidates and kind of the indications you know 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 and expectations.
I was just wondering, on the safety side, wondering if, 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, you know, are most important, for us to pay attention to. Thank you.
Got a lot in there, Greg. We'll start with the first part for Dr. Hu. Dr. Hu, I think the question is just how we're looking at the different progranulin elevating approaches out there.
Yeah, I think overall, because the haploinsufficiency is a driving force for FTD, so if you can boost progranulin, functioning all levels will be beneficial. So, It's a really hard question. I feel like, you know, like, as we kind of discussed earlier, we don't know what is the range that progranulin can be beneficial, and then when you have too much, then you cause the risk of driving cancer progression. So, maybe, I think with the AL101's anti-sortilin approach is manipulating endogenous progranulin. So, and it works at a ceiling, so it won't go super high. Other approaches with small molecules, I'm not really familiar with these clinical trials or the AAV progranulin, so I'm not sure what would be the range of progranulin elevation they are looking at.
And I guess, my kind of main kind of concern would be, you know, really the progranulin level, and overall level, and then maybe it's also distribution. Maybe Dr. Boxer can better answer this question because I think, he might know the other clinical trials better than I do.
Sure. Yeah, I mean, I think that I'm aware of, there are four other clinical trial programs underway in the progranulin space. Three of them are AAV progranulin programs. One is a recombinant progranulin that has a brain shuttle linked to it. You know, 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. You know, if it turns out that a supernormal progranulin 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 concern 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, you know, I think that's the concern in my mind, for AAV right now, even though one and done is attractive in other ways. But, you know, safety-wise, I think this is probably the safest approach. You know, in terms of biomarker, so in terms of safety and INFRONT-3, I don't really have any a priori concerns about the safety. I mean, there haven't been any safety signals to date that I know of that have been meaningful. In terms of biomarker effects, well, you know, the, the ones that we're very interested in are neurofilament, but you said, which is not an ideal biomarker in fluids because it has a very long half-life.
GFAP has a shorter half-life and therefore, and maybe a little bit more specific to progranulin effects on, on the astrocytes in the brain, and so that may be even better. But neurofilament, GFAP, brain atrophy would be, of course, very exciting if they saw a change there. You know, other downstream biomarkers of lysosomal function, but ultimately, as a phase three program, I think you have to see a clinical effect to move forward.
Thank you, Dr. Boxer, and thanks, thanks for the thoughtful question, Greg.
Thank you.
Thank you. And one moment as we move on to our next question. And our next question is going to come from the line of Tom Shrader with BTIG. Your line is open. Please, go ahead.
Thank you, and thank you for another terrific presentation. I wanted to return to Dr. Hu with a little bit with the idea of whether the progranulin is doing what you would want it to do. Does the rate of change of things like lysosomal function and GFAP make 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? I have a follow-up for Dr. Boxer.
Yeah, I think it's anti-sortilin because I think from the cell biology point of view, sortilin is a receptor, a trafficking receptor for progranulin. They're taking progranulin from the Golgi or extracellular space to the lysosome compartment. So when you block this trafficking, you end up with lower, decreased lysosomal pool of progranulin and also the level of granulin peptides, and then with a, you know, accompanying an increase in the full-length progranulin levels, which could be found in the ER, Golgi, or extracellular space. But I think right now, the field, I think we don't know the exact function of the granulin peptide in the lysosome. There are even, you know, reports claiming some of the granulin peptide could be toxic, compared to full-length progranulin.
So really, the difference between progranulin and then granulin peptide, I mean, the full length versus these small peptides, I think I just need more study to figure out the exact function. The extracellular progranulin is kind of, you know, it's in the past, before this association to frontotemporal dementia was found, progranulin is known as a growth factor, you know, functioning like a growth factor manner to drive, you know, inflammation and then tumorigenesis. It promotes cell proliferation. So, this extracellular pool of progranulin, it could have many functions that we have not kind of explored yet.
I feel like the data from Alector kind of suggests that maybe this pool of progranulin might be more important than the lysosomal pool of granulin peptide in at least in this treating patients with, you know, this severe neurodegenerative phenotype already.
Okay, thank you for all the thoughts.
I was just going to comment. I mean, I think we're really encouraged by the changes that we've seen on the markers of lysosomal function, inflammation, astrogliosis. There's still a lot that's not known in terms of what 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 treated a huge number of these patients. How noisy is the primary endpoint in untreated patients over the course of this 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 site-to-site variability is low, or is it complicated? Thank you.
Well, again, most of the people are really progressing very rapidly by the time they're enrolled in a study like INFRONT-3. So yeah, I mean, if someone didn't progress at all over the 96-week trial, that would be huge, because you'd expect really prominent changes over that time in FTLD-CDR sum of boxes. I would note that the CDR sum of boxes is a very common endpoint in Alzheimer's disease trials and has been used in, you know, lecanemab and donanemab, 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 two other domains.
It's not really substantially different in all the same training and reliability, you know, issues that have been, you know, not issues, but, you know, just the good training and reliability that's been demonstrated in Alzheimer's trials applies, I think, also to a program like this.
I can comment perhaps just strictly from a clinical trial perspective. You know, there's a number of things that we employ to try and reduce the noise, whether it be rater training, centralized review of the scoring of the CDR. So there's a number of aspects that we employ to reduce that inter-site variability and even intra-rater variability, 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.
Thank you.
Thanks, Tom.
Thank you, and one moment as we move on to our next question. Our next question is gonna come from the line of Miles Minter with William Blair & Company. Your line is open. Please go ahead.
Hi, you've got Sarah on for Miles. Thanks for hosting a great R&D event and for taking our questions. I've got a couple. So first-
Thanks, Sarah.
Similar to the protective TMEM106 allele changes, are there any evidence of gain-of-function mutations in GRN, the GRN gene or other causes of endogenous elevations of progranulin, like a SORT1 loss-of-function mutation that you guys have seen? And if so, are those mutations protective? I'm less concerned about a, like, enrollment in a trial, but more from a mechanistic point of view.
Yeah. I don't know, Doctor, do you wanna start on that? Maybe we can add from the Alector side, if you have experience there.
So is the question about TMEM106B, whether it's for the protective allele? Sorry, I didn't get the, Can you repeat the question, maybe?
Yeah, sorry. So I'm just curious if there are any gain-of-function mutations in, like, GRN or loss-of-function mutations in SORT1 that lead to endogenous increases in progranulin, and if those are protective, similar to what we see with a TMEM106B?
No, not. I'm not aware of any gain-of-function mutations in granulin.
Meaning the relations between sortilin and progranulin was identified through the genetic polymorphism. So there are polymorphisms in sortilin that has changed the level of progranulin. There are rare people that have heterozygous loss-of-function of sortilin, but there are. So the number of people that display, carry these genetic mutations is too small to really derive any conclusions regarding protection.
I'm gonna have to log off. Are there any last questions for me?
I believe we have one 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.
Okay. Sarah, did you have a follow-up for Dr. Boxer?
Not for Dr. Boxer, but I do have two for the Alector team, if there's time.
Okay.
Okay, great.
We can hang on for those. Maybe, operator, go to our last person on the line, and then we can let Dr. Boxer go.
All right, one moment.
Okay. Go ahead. We can, we can continue with Sara. Thank you.
Oh, great. Thanks. 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 preclinical studies? And is this something you guys are monitoring in the phase 3 study?
It's certainly something that we're monitoring in the phase 3 study. You know, it links back to kind of the strength of the mechanism of action and elevating levels to within a range seen in healthy controls. So, you know, it would be logical to think that, you know, 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, you know, certainly the longitudinal clinical data that we'll have at the end of the day will be telling for that. It's certainly something that we're interested in, we're monitoring, and don't have any signals around to date.
Yeah, no preclinical signals either. There's been no safety signal related to oncogenesis in our program whatsoever.
Great. Thanks for the clarification. And then one more quick one for me. Are there any NfL threshold requirements in the symptomatic patient in INFRONT-3, or is that something you guys are just looking at in the presymptomatic patient? Thanks.
Yeah, only in the presymptomatic patients, so no, NfL requirements for eligibility in the symptomatic individuals.
Great. Thanks so much.
Thank you, Sara. And operator, I think we have time for one more.
All right, just one moment, please. Our last question will come from the line of Neena Bitritto-Garg with Deutsche Bank. Your line is open. Please go ahead.
Hey, guys. Thank you so much for taking my question and squeezing me in here at the end. So I just wanted to ask a kind of theoretical question about just a read-through from some of the biomarker data that you've seen to date to, you know, 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, you know, potential in Alzheimer's and other diseases where there is a TDP-43 component. Thanks.
Yeah, thanks, Nina. That's too bad we lost Dr. Boxer there, because I'm sure he would've helped there with the perspective. It's great to have you back. I don't know, Dr. Hu, if you have any comments there, or Arnon, others want to comment?
Not really. I mean, I know TDP-43 is, you know, kind of found in both FTLD and, it's pretty common for AD as well, but, yeah. Sorry, I don't have any knowledge about the clinical side.
Okay. Arnon or Gary, if you want to add more?
Yeah, I mean, in general, if we see efficacy in one indication, it will suggest that the drug is effective. It's sort of elevating progranulin to the right level. It's elevating progranulin in the right places. 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 will still have to do clinical trial in each indication to show efficacy.
This is Gary Romano. Yes, but especially in the FTD in the TDP-43 indications. You know, if that, we know that in FTD-GRN, it's, it's we do have a, you know, it's TDP-43 pathology. That's really why, you know, there are interest in ALS, in C9, and even in Alzheimer's disease or LATE disease, you know. So, you know, we're, we're eagerly waiting for biomarkers of FTD for TDP-43, so that we can, you know, assess that. I think that's coming pretty soon, hopefully. But yeah, but definitely a positive result in this phase 3 study would, you know, would, it, would, you know, would increase the interest of us and our colleagues at GSK. I think I can speak for them that way.
Got it. Thank you.
Okay. Thank you, Neena, and thanks, everyone.