Good morning, ladies and gentlemen, and welcome to Alector's conference call and webcast highlighting its progranulin franchise and Alector Brain Carrier programs. 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, and to participate, simply press star 11 on your telephone and press star 11 again to remove yourself. Now, I would like to turn the call over to Katie Hogan, Senior Director of Corporate Communications and Investor Relations. Please go ahead.
Hello, everyone, and welcome to our event. Before we begin, I will go over a few housekeeping reminders. There will be a moderated question-and-answer session following prepared remarks. To submit the 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 in the Investor section under Events and Presentations on our website, www.alector.com. I'd like to note that during this event, we'll be making a number of forward-looking statements, and you can find our disclosure here. Turning now to the agenda, we'll begin with an overview from Dr. Sara Kenkare-Mitra, our President and Head of Research and Development. She'll share Alector's perspective on our multi-stage pipeline and our approach to driving value in treating neurodegeneration.
Sara will then provide a review of our progranulin-elevating franchise in FTD-GRN and Alzheimer's disease, highlighting latozinemab and AL101, formerly AL-101, which we are developing in collaboration with GSK. From there, our Chief Executive Officer, Dr. Arnon Rosenthal, will discuss advancements in Alector Brain Carrier and introduce our lead candidates for Alzheimer's and Parkinson's. With that, I'll now turn it over to Dr. Sara Kenkare-Mitra. Sara?
Thank you, Katie. Alector is dedicated to developing first and best-in-class disease-modifying therapies for neurodegenerative diseases with urgent unmet needs. We're building an integrated biotech that brings together expertise in genetics, immunology, and neuroscience with deep capabilities in discovery, development, and manufacturing. Our therapies are designed to address the root causes of disease. Our 3R strategy aims to remove misfolded proteins, replace deficient proteins, and restore dysfunctional immune cells and neurons. This strategy is powered by advanced technologies, including our proprietary Alector Brain Carrier, or ABC, which improves therapeutic delivery across the blood-brain barrier. With our clinical late-stage progranulin-elevating antibodies in partnership with GSK, a growing pipeline of ABC-enabled programs, strong cash resources, and an experienced leadership team, we are positioned to drive both near and long-term value. Our progranulin-elevating programs form the foundation of our late-stage portfolio.
Latozinemab in development for FTD-GRN has received breakthrough therapy, fast track, and orphan drug designations, and top-line phase 3 data are expected by mid-Q4 of this year. Alongside it, AL101 in Alzheimer's disease is fully enrolled in a phase 2 trial. In parallel, we have selected lead candidates for our ABC-enabled anti-amyloid beta antibody program for Alzheimer's disease and our ABC-enabled GCase enzyme replacement therapy for Parkinson's disease. We are also progressing ABC-enabled siRNA programs for tau, alpha-synuclein, and NLRP3 for multiple neurodegenerative diseases. This portfolio provides an important near-term milestone within our late-stage programs. It also includes the potential for the initiation of first-in-human trials from our ABC-enabled pipeline in 2026 and 2027. Let me now turn to our GSK-partnered progranulin-elevating franchise, which targets frontotemporal dementia caused by GRN mutations in Alzheimer's disease.
Frontotemporal dementia. While Alzheimer's disease is the most common form of dementia, you may be less familiar with frontotemporal dementia due to a granulin mutation or FTD-GRN. FTD-GRN is an aggressive, early-onset dementia. Patients often present with compulsive behavior, lack of restraint, apathy, anxiety, or aphasia. Tragically, life expectancy is typically less than 10 years, and there are no approved treatments to slow or cure the disease. Heterozygous loss-of-function mutations in the granulin gene reduce the levels of a protein called progranulin by 50%, directly causing the disease. In partnership with GSK, we are developing latozinemab, which is designed to elevate progranulin levels back to physiologic levels. FTD is rarer than Alzheimer's disease, but it is the most common cause of dementia in individuals under the age of 60, and most cases occur between the ages of 45 and 64.
In the U.S., the prevalence is estimated to be approximately 50,000 to 60,000 people, and in Europe, the number is closer to 110,000. FTD GRN accounts for approximately 5% to 10% of all FTD cases and represents about 8,000 to 17,000 cases in the U.S. and EU alone. Importantly, the overall economic burden per patient for FTD is nearly twice that of Alzheimer's disease, underscoring the urgency of developing effective therapies. FTD GRN is frequently misdiagnosed as Alzheimer's disease, Parkinson's disease, Lewy body dementia, vascular dementia, or unspecified dementia, as you can see in the bottom half of the table. This underscores the importance of genetic testing to ensure patients are properly identified and can access future therapies. As we have seen in other therapeutic areas, once disease-specific treatments become available, the uptake of genetic testing typically increases.
That means the landscape for FTD-GRN diagnosis could shift meaningfully as potential therapies move closer to approval. Both latozinemab, being developed for the treatment of FTD-GRN, and AL101, or formerly AL-101, being developed for the treatment of Alzheimer's disease, are designed to increase progranulin levels by blocking sortilin, a receptor that binds progranulin and directs it to the lysosome for degradation. Progranulin, encoded by the GRN 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. Human and mouse data shown on the left side of the slide demonstrate that higher sortilin levels mean lower progranulin. By inhibiting sortilin, our antibodies increase extracellular progranulin levels. The rationale for progranulin-elevating drugs in FTD is clear.
On the left, we show the 50% reduction in plasma and CSF progranulin in granulin mutation carriers and patients compared to healthy controls. This deficiency triggers a neurodegenerative cascade, neuronal cell death, and microglial dysfunction, leading to TDP-43 accumulation, lysosomal impairment, complement activation, and inflammation. These processes result in destruction of brain structures, ultimately driving the cognitive and behavioral deficits seen in FTD. Latozinemab is designed to elevate progranulin levels in the brain, addressing the underlying deficiency that contributes to neuronal loss, inflammation, and cognitive and behavioral deficits in FTD-GRN. The rationale for progranulin-elevating drugs in Alzheimer's disease is also compelling. Human genetics show that loss-of-function mutations in progranulin increase Alzheimer's disease risk, while preclinical studies demonstrate that elevating progranulin can be protective. On the left, human genetic data highlights granulin as a risk gene for Alzheimer's disease.
In the center, immunohistochemistry shows progranulin embedded within amyloid beta plaques in Alzheimer's disease brain tissue, emphasizing its association with disease pathology, and on the right, data from AD mouse models shows that increasing progranulin improves disease-relevant outcomes. These findings together provide strong genetic, pathologic, and preclinical support for evaluating a progranulin-elevating drug, AL101, in Alzheimer's disease. The genetic and biologic rationale for blocking sortilin to elevate progranulin in FTD-GRN is grounded in multiple lines of evidence. Loss-of-function mutations in SORT1 lead to chronically elevated progranulin in humans and mice with minimal or no discernible adverse effects, providing a strong genetic foundation for this approach. Biologically, progranulin that does not bind sortilin can still enter lysosomes through alternative receptors, where it remains partially active and supports neuronal survival. You can see this in the images on the upper left.
Even in SORT1 deficient cells shown in the bottom panel, progranulin continues to traffic to lysosomes, similar to wild-type cells in the top panel. The schematic next to it illustrates how multiple receptors facilitate lysosomal entry in the absence of sortilin. Importantly, progranulin that is mutated to bypass sortilin appears more potent than wild-type progranulin in rescuing microglial pathology, reducing NfL, and correcting lipid abnormalities in mice. Experimental data further support this strategy. The graphs on the bottom left show results with AL101, our antibody that blocks sortilin to elevate progranulin. In this first panel, AL101 nearly eliminates functional sortilin, confirming target engagement. This is accompanied by significant increases in progranulin levels in plasma and CSF, as shown in the middle and right panels, and these findings demonstrate that blocking sortilin effectively elevates progranulin and restores key functions of progranulin.
Together, these genetic, biological, and experimental data establish a compelling case for targeting sortilin to increase progranulin and address neurodegenerative disease mechanisms. It's important to note that latozinemab and AL101 target distinct regions or binding epitopes on the SORT1 protein. The PKPD profile distinguishes AL101 from latozinemab. 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. Both latozinemab and AL101 have demonstrated a two- to three-fold increase in progranulin levels and have been generally well tolerated in clinical trials to date. Turning now to clinical data in our progranulin-elevating antibodies, I will begin with our INFRONT-2 phase II study of latozinemab, which was designed to gather data on safety, PK, PD, clinical outcomes, and biomarkers.
In the trial, 12 symptomatic FTD-GRN patients were treated with latozinemab at 60 mg/kg every four weeks for 49 weeks. To determine whether there was treatment-related slowing of disease progression, we used historical data from the GENFI-2 and all FTD non-interventional registry databases to generate a matched control cohort that would allow us to make comparisons to FTD-GRN participants in our open-label interventional cohort. In INFRONT-2, we evaluated three areas: target engagement through progranulin levels in plasma and CSF, biomarkers of disease activity, including lysosomal function, inflammation, brain health, and atrophy, as well as clinical progression measured with CDR plus NACC FTLD, a tool designed for FTD. We'll now review some of the key findings. In INFRONT-2 study, latozinemab increased progranulin in plasma and CSF 2 to 3-fold, restoring levels to those seen in healthy controls and sustaining them over 49 weeks.
Also, plasma and CSF concentrations were strongly correlated, supporting the use of plasma progranulin as an important biomarker for use in clinical trials. Here we show the INFRONT-2 data for GFAP, or glial fibrillary acidic protein, a marker of astrogliosis that is elevated in symptomatic FTD-GRN and correlates with disease severity. These figures show that GFAP levels are elevated in symptomatic FTD-GRN patients at baseline and that at treatment, GFAP levels decline over the course of the study towards the range seen in asymptomatic GRN mutation carriers. We also looked at disease progression using the CDR plus NACC FTLD, a measure of clinical progression in FTD agreed upon by the FDA and EMA. In matched controls from the GENFI-2 registry, patients declined by 6.4 points over 12 months.
By contrast, participants treated with latozinemab declined by 3.1 points over the same period, which represents an estimated 48% slowing of clinical progression compared to matched historical controls. In INFRONT-3, our pivotal phase III trial, we are measuring the same clinical measures and core biomarkers that we assessed in our INFRNT-2 phase II trial. INFRONT-3 is a 96-week randomized double-blind placebo-controlled global trial evaluating latozinemab in 103 symptomatic and 16 at-risk individuals with confirmed GRN mutations. Participants receive 60 mg/kg or placebo via intravenous infusion every four weeks. The primary analysis will be conducted in symptomatic participants, and we plan to include at-risk participants in a sensitivity analysis. The clinical coprimary endpoint is the CDR plus NACC FTLD sum of boxes, and in the U.S., the biomarker coprimary endpoint is plasma progranulin.
Additionally, we are measuring key secondary outcomes, assessments, and collecting fluid and imaging biomarkers, including plasma NfL, GFAP, and volumetric MRI. We believe this positions us to deliver a clear and well-aligned data package later this year. Our phase II study of Mivysnuvart in early Alzheimer's disease is ongoing. In partnership with GSK, we completed enrollment of that study in April. An independent interim analysis is expected in the first half of 2026. PROGRESS-AD is a global, randomized, double-blind placebo-controlled phase II clinical trial enrolling patients with early Alzheimer's disease. The study is designed to assess the safety and efficacy of two-dose levels of Mivysnuvart compared to placebo. Participants are randomized to receive Mivysnuvart or placebo intravenously every four weeks for the duration of the 76-week trial.
The primary endpoint of the study is disease progression as measured by the clinical dementia rating sum of boxes or CDR sum of boxes. We are also measuring key secondary endpoints and biomarkers, including amyloid PET, tau PET, and biomarkers in CSF and plasma. Our progranulin programs, latozinemab and AL101, are being developed in partnership with GSK. This partnership included $700 million in upfront payments and includes a $1.5 billion in potential development and commercial milestones, a 50/50 U.S. profit share, and tiered 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 first commercial sale in at least two of the EU countries. With that, I'll turn the call over to Arnon to discuss our preclinical programs enabled by the Alector Brain Carrier.
Thank you, Sara, and welcome, everyone.
I will now guide you to a tour to an imminent future, which is propelled by Alector Brain Carrier. Alector Brain Carrier is using the transferrin receptor on the blood-brain barrier endothelial cells to deposit and transport cargo to the brain. There are three features of Alector Brain Carrier that I'll first mention. First is that our brain carrier module is completely independent. It can be placed in multiple places on the target. On the left here, you see placing the brain carrier on the constant region of the antibody with a linker. The linker can be of any size or no linker at all. In the middle figure, you see us placing the brain carrier module as part of the FAB configuration.
On the right, on the bottom, you see that we can place the Alector Brain Carrier as part of a single RM antibody or as part of a Fab. Our Alector Brain Carrier can be bivalent, as you see on the left bottom, or monovalent. This flexibility really enables us to tailor the drug to the different drug modalities, be it antibody, enzymes, or nucleic acids. The configuration of the drug really dictates the drug half-life, immunogenicity, and brain penetration. This is an important tool to optimize blood-brain barrier-propelled drugs. The next feature of Alector Brain Carrier is the large variability or the large range of affinities that we can deploy. As you see on the left table here, we have almost a thousand-fold range of affinities from five nanomolar to almost 5,000 nanomolar. Again, the affinity dictates hematologic adverse effects, drug half-life, and brain penetrant.
This large range of affinity enables us to tailor the affinity to each drug modality and specifically within each drug modality to each drug and gives us a real unique tool to optimize ABC-propelled drugs. The third unique feature of our platform is the epitope that they are using to engage the transferrin receptor. Whereas many blood-brain barrier technologies are using an epitope which we consider to be exposed on the transferrin receptor, we have identified a different epitope that is depicted on the left side of the structure of the transferrin receptor. And this epitope is between two lobes. And the uniqueness of these epitopes is that it is reducing the ability of ABC-propelled drugs to induce transferrin and antibody-dependent cellular cytotoxicity. This is apparent on the right graph.
You're seeing in the red line using the exposed epitope, which we call an epitope B, which many other companies are using. This enables the antibody to facilitate ADCC that is transferrin receptor-dependent. In contrast, when we use our own epitope that's depicted on the graph in green and yellow here on the right, you see a significantly lower ADCC. This really provides a unique safety feature for our drugs. We think that reduced ADCC would translate to reduce hematologic adverse effects and increase safety of our ABC module. With these ABC features, we are developing, as Sara mentioned to you, three types of drug modalities. We are developing antibody drugs that are propelled by ABC, enzymes that are propelled by our ABC, as well as multiple siRNAs that are propelled by ABC. I will start by describing our antibody against the amyloid beta that's an ABC-enabled.
Every aspect of our anti-Aβ antibody, which we designate as AL037, was engineered to optimize efficacy and tolerable pharmacokinetics and safety. The anti-Aβ binding epitope was engineered to recognize the pyroglutamate version of the Aβ peptide, as was shown by Lilly. Targeting the pyroglutamate Aβ was the most effective in reducing Aβ plaque rapidly, and there is no Aβ pyroglutamate in the circulation in the serum. This is minimizing systemic effects and retention of the antibody in the periphery. We undertook or chose to retain a fully functional effector function. We think that recruiting myeloid cells through the effector functions is critical to fully remove beta amyloid plaques and that the effector function cannot be substituted by the transferrin receptor or by a crippled effector function. We are targeting to maximize removal of Aβ plaques with a full effector function.
We then added to this drug our optimized ABC technology, which is designated to maximize brain penetrations and minimal hematologic adverse effects, as well as maximize pharmacokinetics in the serum. I will now show you some data with this drug. The first thing that we did is to confirm that AL037 can really transcytose through brain endothelial cells, and on the left side, you see a cell culture assay with brain endothelial cells where you can put the drug on the top, on the apical side, the blood side of the culture, and then you can measure how much of the antibody can move to the basolateral side, the brain side. You can see in the middle panel here that naked AL037, this is an antibody that does not have the ABC module, is not able to cross through the endothelial cells.
In contrast, AL037, which does have the ABC module, very readily being transduced through the endothelial cells, and this is quantified on the graph on the right. A very significant part of the antibody reaches the basolateral of this culture, of this transfer culture, suggesting that it will be able to translate those to the brain in vivo. The next thing that we confirmed was the ability of AL037 to phagocytose those Aβ peptides, and on the left side here, you see images of human microglia, phagocytosing fluorescent Aβ and internalizing it, and again, you see that AL037 is very effective in phagocytosing Aβ. On the right side, there is quantification of this phagocytosis event. You see that naked AL037 in orange here can phagocytose those Aβ plaques, but the blue, which represents AL037 with the ABC module, can phagocytose those Aβ plaques even better.
This suggests that the ABC module can contribute to phagocytosis, but it's still incremental, and you still require a full effector function including the Fc gamma receptor for full phagocytosis. We next moved in vivo. We first tested AL037 in mouse models of Alzheimer's disease. This is the 5X FAD mice. You see on the left picture, this is the light sheet microscopy. You see that the naked antibody primarily gets stuck in the ventricle and in large blood vessels and is not distributed well into the brain. In contrast, the three right graphs show antibodies that are enabled by our ABC. In all cases, you see that there is no longer stickiness into ventricles and blood vessels. There is homogeneous distribution in the brain. On the two right panels, you see that our antibodies can detect Aβ plaques very well and really bound to them.
The rightmost pictures show a three-dimensional reconstitution. You see antibodies recognize practically all the plaques in this brain or many of the plaques and can sort of recognize and bind to them. AL037 not only bound to plaques, it also stimulates microglia-dependent removal of plaques, and this is seen on the graphs on the right. You see that even after three to four injections of the antibody, in a very short time frame, you see significant reduction in the level of Aβ42 in the brain, so antibody at fairly low doses is able to penetrate the brain, distribute homogeneously, and remove Aβ42 in a very short duration. With the mouse data at hand, we advanced to non-human primate studies. The first thing that we looked at was the half-life of AL037.
You see in two doses, 30 mg per kg and 3 mg per kg, we see that the half-life of AL037, which is linked to our ABC, is about 106 hours. This is significantly better than reported brain shuttle-linked antibodies. It's actually not far off from a naked antibody like a normal antibody. We do show a very decent half-life of the antibodies in non-human primates. The next thing that we looked at was hematologic side effects. As you know, there are 10 times more transferrin receptors expressed on the reticulocytes compared to endothelial cells. All brain shuttle technologies that are using transferrin receptors have an inherent risk of hematologic side effects. We measured that. As you see on the left graph, we do see transient reduction in reticulocytes, but the reticulocytes recover very quickly within a day.
Even after two injections at day one and day eight, we don't see a meaningful reduction in red blood cells in the middle graph or in hemoglobin in the right panel. We see a very tolerable safety profile for AL037. We next looked at brain penetration in the non-human primates. To our delight, we saw very potent brain penetration. As you see on the left panel in the frontal cortex, even at three mg per kg, which would be around the range of all the clinical doses, we see 18-fold elevation in brain penetration. We see it in every brain region that we tested. Here we show just the frontal cortex on the right, on the left, and hippocampus on the left. There is a homogeneous distribution of AL037 in the non-human primate brain.
If you calculate the molarity of brain level, you see that our AL037, even at 3 mg per kg, can reach a 3.8 nanomolar in the brain, and this is, according to our calculations, at least five times higher than what was reported for other brain shuttle antibodies that are currently in the clinic, so we see a very potent high concentration in the brain that suggests that this antibody would be very effective at removing Aβ plaques in humans. Given the significance of Alzheimer's disease as an unmet medical need, we are developing a second anti-Aβ antibody, which we designate as AL137. This antibody is deploying a different ABC modality with higher affinity, and we see that in this case, we can achieve 32-fold increase in brain level, and this 32-fold increase can translate to 8.4 nanomolar, even at 3 mg per kg in the brain.
This is over 12 times higher concentration than what, according to our calculations, was reported for clinical brain shuttle anti-Aβ antibodies. We have, again, an even more potent anti-Aβ antibody, which has still very, very good pharmacokinetics and tolerable safety features. To summarize what I've shown you on our anti-Aβ programs, we have two anti-Aβ antibodies, AL037 and AL137, that target the pyroglutamate anti-Aβ peptide, which in our view, and as was demonstrated by Lilly, is the most potent epitope for removal of Aβ plaque. We retain a fully active Fc region to enable full function of recruitment of myeloid cells to remove Aβ. We have an optimized ABC module that can lead to high brain penetration, but still good hematologic safety and good pharmacokinetics. We think that we have two uniquely potent and safe antibodies that could really be best in class in anti-Aβ therapeutics.
We are targeting first in human in 2026. The next program that I will describe is our brain carrier-enabled GCase enzyme replacement therapy for Parkinson's disease and eventually Lewy body dementia. As you know, GCase or GBAs are lysosomal enzymes that remove toxic substrates, toxic lipids like glucosylceramide and glucosylsphingosine from cells. And if you don't have functional GCase, these toxic lipids accumulate and cause diseases. There are up to 10-15 million people that have Parkinson's disease that carry the GCase mutations. This translates to up to 1.5 GBA mutation carriers with Parkinson's. There are up to 2.4 million GBA mutation carriers that suffer from Lewy body dementia. And there are over 100,000 Gaucher disease patients with the GBA mutation. As you know, currently, there is enzyme replacement therapy for Gaucher disease, which displays peripheral symptoms.
There is no enzyme replacement therapy for Parkinson's disease or Lewy body dementia because current enzyme replacement therapy cannot enter the brain. Even if it enters the brain, the way it enters cells does not allow us to enter. It does not allow it to enter nerve cells or myeloid cells in the brain. Even though we are starting with genetic mutation carrier, there is really good evidence that GCase enzyme replacement therapy could be also beneficial for the sporadic form of Parkinson's disease and likely Lewy body dementia.
The reason is that if you look at all primary Parkinson's patients, if you measure the level of GCase activity versus the rate of disease progression, you see in the yellow line on the left graph that people that have high level of GCase activity show low progression rate, whereas people that show low level of GCase activity in the dark line display very high progression rate, and consistent with the level of enzymes you see on the right graph here, in blue, people that have low level of the toxic lipids show slow progression rate, whereas people with Parkinson's disease, regardless of whether they carry the genetic mutation or not, people that have high level of the toxic lipids display very rapid progression rate.
So this really suggests to us that even in sporadic form of Parkinson's disease, brain-penetrating GCase enzyme replacement therapy could be beneficial to slow disease progression. So as we did with AL037, we did for AL050, we engineered every component of the drug. We first engineered the enzyme itself. The wild-type GCase enzyme has very short half-life. It is very unstable, and it's hard to manufacture. So we engineered GCase that are almost 30-fold more stable than the wild-type. You can see it on the table. On the left bottom, you see that wild-type enzyme has a half-life at 37 degrees of six hours versus seven days of our enzyme. Likewise, we engineered the enzyme to have almost 50-fold higher activity. You see this is a logarithmic scale. You see the activity of the wild-type enzyme versus AL050.
We designed a very potent and stable engineered GCase as the first component of the drug. We then linked it to an optimal ABC that has a higher affinity that enabled fast removal, a fast transport to the brain. As I'll show you also, transport to cells and to the lysosomes in brain cells. Finally, because we don't need to recruit immune cells, we silenced the effect of function of this drug to minimize or eliminate hematologic-related adverse effects. We took this drug initially to testing in cell culture. The first thing that we did was to confirm that AL050 can enter lysosomes in cells. As you may know, the peripheral enzyme replacement therapy is using macrophages' mannose receptor to enter cells. Current enzyme replacement therapy for GCase, the protein can only enter macrophages in the periphery.
It cannot enter nerve cells, and it cannot enter microglia cells or other cell types in the brain. So first, we wanted to see whether we can substitute the mannose receptors with the transferrin receptor. And we saw that this is indeed the case. You see here that our GCase that is propelled by ABC can enter the lysosomes. And you see overlay of fluorescent staining with lysosomal markers like LAMP1. So on the left side, we show that our GCase propelled by our ABC can enter cellular lysosomes. And these are neuronal cells that the regular enzyme replacement therapy for GCase will not be able to do. On the right side, we also looked at activity of the GCase in this lysosome. And we see that there is very potent GCase activity in these GCase-deficient neuronal cells. And the level of activity is transferrin affinity dependent.
So the higher affinity the ABC model, the higher the activity. And you see that with affinity that we are using for the clinical program, we are easily exceeding the wild-type level of GCase activity, which is marked in the gray horizontal bar on the right graph. So based on the cell culture activity, we found out that we have a very potent and active enzyme. And we have a drug that can enter lysosomes in neuronal cells and can retain activity in neuronal cells. With this information, we took our drug to non-human primates. We first tested the half-life of our drug in the non-human primate plasma. And as you see on the left graph, AL050 displays a half-life of five hours. And this is compared to current enzyme replacement therapy that's sort of illustrated on the right side of this slide.
Current enzyme replacement therapy displays a half-life of less than 30 minutes. So in this experimental paradigm, at least, AL050 displays 10-fold higher, longer half-life in the plasma compared to current enzyme replacement therapy. We then looked at the enzymatic activity in the non-human primate plasma. And we see on the left side here that AL050 delivered a 10-week peripherally displayed half-life of activity of 6.6 hours. And again, this is almost 40-fold longer than the enzymatic activity that was reported for current enzyme replacement therapy, where the serum half-life of enzymatic activity is about 10 minutes at a maximum, even in humans. So at least with these experiments, we show that both in vitro, biochemically, in cell culture, and in non-human primates, we have a stable and an active drug that retains enzymatic activity extracellularly.
This will allow time for the drug to enter the brain and possibly retain activity in the brain. These are the things that we looked at next. Before we did that, we sort of looked at the safety of AL050. Again, all brain shuttles that use transferrin as the Trojan horse have a risk of hematologic side effects. So we wanted to make sure that this is not the case with 050. You see on the left graph here, AL050 does not lead to any meaningful reduction in reticulocyte count after two injections. Likewise, there is no effect on red blood cell count and no effect on hemoglobin in this experiment, suggesting that AL050 will be safe with regard to hematologic adverse effects. We next looked at what happens in the brain.
The first thing that we looked at was whether our ABC-propelled AL050 can actually enter the brain, basically cross the blood-brain barrier and enter tissues in the non-human primate brain. We see that this is indeed the case. You see that in every brain region that we looked at, the frontal cortex, hippocampus, as well as brain regions that are relevant for Parkinson's disease and Lewy body dementia, the substantia nigra, where the dopaminergic cell body resides, and the putamen, where the dopaminergic nerve endings are. We show a very good level of AL050 that's sort of somewhere between six and 20-fold elevation of enzyme. We then looked at enzymatic activity. Again, for enzymatic activity, our AL050 has to enter the brain, has to enter neurons and support cells in the brain, has to enter lysosomes in these cells, and then has to retain activity.
This is a very significant demand for a drug. We were not sure that this would happen. But to our sort of delight, it did happen. You see that in all brain tissue that we looked at, again, including the substantia nigra and the putamen, which are relevant brain regions for Parkinson's disease and Lewy body dementia. We see at least twofold elevation in GCase activity. Parkinson's patients and Lewy body dementias have modest reduction in their GCase activity, somewhere between 15%-50% reduction. Doubling the level of GCase activity would be more than sufficient to fully repair enzyme deficiencies in these diseases. Moreover, we think that there is some negative regulation feedback on lysosomal enzymes.
In healthy brains, like in the non-human primate brain, a high level of GCase enzymatic activity could lead to reduction in the level enzymatic activity of the endogenous GCase. We think that in patients, this level could be even higher. Although, again, as I mentioned, twofold elevation is significantly more than what is needed to fully restore GCase deficiency in Parkinson's patients and Lewy body dementia patients. We then wanted to see whether our drug can actually correct disease pathology. For this, we went back to mice. These are mice that carry one of the Parkinson's GBA mutations, D4092V changes. This mutation reduces GCase activity by 85%. On the left bar graph, you see the level of GCase in wild-type mice. This is in the gray.
You see on the right side of the left panel. You see that the mouse mutation models that were treated with TBS do not show hardly any GCase enzymatic activity. However, once we inject AL050 surrogate, we see almost complete restoration of GCase activity. This is just 24 hours after one injection. You see almost complete restoration of enzymatic activity. We went further and looked whether the increase in enzymatic activity is also associated with reduction in toxic substrates. This was done initially in the periphery, in liver. I'll show you data in the brain in the next slide. Again, you see on the right panel, the right graph. Wild-type animals do not have toxic substrates because the endogenous GCase get rid of them. However, GBA mutation carriers have a very high level of toxic substrates, as you see from the blue bar graph here.
But even sort of two injections of AL050 surrogate reduced these toxic substrates by almost 90%, suggesting that at least in the periphery here, our drug is very active, can enter cells, and can restore enzymatic activity, and can remove the toxic lipids that cause the diseases. We then wanted to see if the same thing can happen in the brain of this GBA mouse mutant. And what we found out is that this is indeed the case. You see on the left panel of bar graphs, this is still a wild-type mice that carry the human transferrin receptor. But they have a wild-type level of normal level of GCase. And you see with TBS, this is in gray. This is the normal level of GCase. But if you inject AL050 surrogate, you almost double the level of GCase activity in the mouse brain.
We then went to GBA mouse mutants. Again, in the middle graph, you see that wild-type mice injected with TBS does not show any toxic substrates because the endogenous GCase take care of these. In contrast, GBA mutant mice show a high level of toxic substrates, as you see from the blue bar. And two injections of AL050 surrogate reduce the toxic substrate by 80%. And again, the enzyme will continue to work. So two injections is a very short and acute timeline. And we think that over time, the reduction will be even more profound. Although 80% reduction in the toxic substrate, we think could be significantly therapeutic. We wanted to look at the durability of the effect on the right panel here.
We see that even after a single injection, the reduction in the toxic substrate can last for over 14 days, suggesting that once our enzyme gets into the lysosome, it retains activity for multiple weeks, way beyond the residence in the plasma. Just to summarize what I've told you, we have engineered AL050 to have multiple beneficial drug features. It has engineered GCase that are 30-fold more stable and 50-fold more active than the wild-type GCase that show long half-life and long enzymatic activity in the non-human primate serum. We show that AL050 can enter the non-human primate brain, enter nerve cells and support cells in the brain, enter the lysosomes, and retain enzymatic activity.
We think that we have a pretty potent drug that could be beneficial for, again, Parkinson's patients that carry the GBA mutations, Lewy body dementia patients that carry the GBA mutations, and eventually sporadic forms of these diseases. We are targeting first in human in 2027. I will just now describe our progress with Alector Brain Carrier-enabled siRNA programs. As you know, siRNA is becoming a very successful drug modality. I think that sort of there are over 20 approved sort of siRNA or ASO drugs. Now, most of them are for peripheral indications. There are two nucleic acid drugs that are approved for central indications, for ALS and for spinal muscular atrophy. The issue for nucleic acid or siRNA for brain disorders is that you have to deliver it by IT or ICV injection. This is a surgical process that is not safe.
It's not highly sort of scalable for large diseases like Alzheimer's disease, and also, with IT or ICV delivery, the nucleic acid is not distributed equally throughout the brain, so some brain regions which are close to the injection sites receive more nucleic acid drugs, whereas regions which are further away from the injection sites receive or deep in the brain receive maybe insufficient drug, so we are undertaking to change that by enabling peripheral delivery of siRNA using our ABC technology, so we screened very extensively, as you see on the second from the left column, we screened a very large range of transferrin affinities with different types of linkers, with different types of drug modalities to identify a good ABC carrier for siRNA, and this was really enabled by the versatility of our technology where we can put the ABC module everywhere practically on the drug.
We can use linkers or not use linkers. We can use cleavable linkers or non-cleavable linkers. We can use different affinity, and we can use different valency. And this has really enabled us to optimize the siRNA delivery. As you see on the third column from the left, we are able to achieve over 40-fold increase in siRNA delivery in the brain following peripheral injection. And the first thing that we did was to look at superoxide dismutase as a proof of concept strategy. And again, with siRNA to superoxide dismutase, we see with different ABC modules, we see 30-40-fold elevation of siRNA in the brain. And we also see, as depicted in the right column, very good long plasma half-life.
We then wanted to see whether our ABC-propelled siRNA enters the brain, enters cells in the brain, and enters the cytoplasm of the cells, and is really able to suppress, to downregulate siRNA. Again, these are very demanding requests from a drug. We inject the drug peripherally. It has to go through the endothelial cells, like to two membranes of the endothelial cells, to go through membranes on nerve cells and support cells, and to enter to the right subcellular localization to access the messenger RNA for, in this case, SOB, and to downregulate it. And to our delight, we saw that our drug is able to do that. If you see every brain region that we looked at, the thalamus, cortex, hippocampus, brain stems, cerebellum, spinal cord, and striatum, in all cases, we see reduction in the SOB mRNA by up to 80%.
This is depicted by the purple and blue graphs that represent our peripherally injected siRNA with two different ABC modules. The purple graph represents ICV injected naked siRNA. You see that in all cases, peripherally injected siRNA with ABC is at least as good as ICV injected siRNA. In most cases, it's significantly better. If you see in the cortex, in the spinal cord, in the brain stem, you see that our peripherally delivered siRNA is better than siRNA injected ICV. This really tells us that we could peripherally deliver siRNA, achieve homogeneous distribution in the brain, convert surgical procedure of ICV or IT into either easily delivered infusion centers or ultimately even at-home delivery with IV or even subcutaneous delivery. We think that there is significant potential for this technology to increase ease of use, safety, and also efficacy.
With this technology, we are now developing three programs. We are developing Tau siRNA with ABC for Alzheimer's disease and frontotemporal dementia that is caused by Tau pathology. We are developing alpha-synuclein siRNA for Parkinson's disease and Lewy body dementia. And we are developing NLRP3 siRNA for multiple neurodegenerative diseases. As you know, NLRP3 is an inflammatory mediator that is thought to be involved in practically every neurodegenerative disease from Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease. And so far, small molecules for NLRP3 were not as effective in the clinic, partially because of off-target activity and partially because of incomplete blockade. So we think that all of these three programs have a very profound potential in very large diseases. Just to summarize what I've told you today and what you heard from Sara, we have a good mix of late-stage and late preclinical programs at Alector.
Our late-stage programs have a program in phase three that is pivotal phase three where we receive breakthrough therapy designation and fast-track designation. We will have data in the middle of Q4 2025. Because of the designations that the drug gets, we think that we can proceed if the drug justifies that we can proceed to BLA rapidly and to commercialization. We have commercial rights in the U.S., so we will be leading commercialization of this drug. Our partner will lead commercialization ex U.S. Our second drug, as Sarah told you, is in early Alzheimer's disease. It has sort of completed recruitment. It is 76% in April. It is a 76-week-long trial. If you calculate, you see that trial completion is in 2026, and we expect to have data shortly after.
In addition to our promising late-stage programs, we have, as I described to you, multiple late preclinical programs that involve antibodies that are propelled by our ABC. I described the anti-A beta antibody, but we also are advancing anti-Tau antibody. We have enzymes that are propelled by ABC for Parkinson's disease, Lewy body dementia, and essentially Gaucher disease with neurological pathology. And we have an emerging platform of siRNA that are propelled by our ABC. These include currently siRNA for Tau, for alpha-synuclein, for NLRP3. But if successful, there are many more targets that would benefit from our ABC modules. Again, as Sara described to you, we are completely focused on neurodegeneration.
We are going after the core of the disease by developing tools to replace damaged or mutated proteins with enzyme replacement therapy, removing misfolded proteins with antibodies and siRNA, and restoring damaged neurons and support cells by antibodies that stimulate signaling in these cell types. We have still over $300 million in the bank that will enable us to complete the two late-stage programs and to take at least two of our preclinical programs to first in human. And we are targeting, again, to have multiple catalysts in both late and early-stage programs in the next one to two years. So thank you, everyone, for listening, and we will now open the webinar for questions.
Thank you so much. And as a reminder to ask a question, simply press star 11 on your telephone. To remove yourself, press star 11 again. One moment for our first question.
It comes from the line of Pete Stavropoulos with Cantor Fitzgerald. Please proceed.
Hello, and thank you for hosting this event. Very informative and great to see all this activity across the pipeline. Our first question has to do with INFRONT-3, as you have the phase 3 reading out, and it's top of mind. Can you just discuss some of the conversations and data that you provided to the FDA that helped enable progranulin as a co-primary endpoint and the sense that you received that they could possibly lean on it for an approval if clinical outcomes were trending in the right direction, but not to that sake?
Thanks, Pete. I think I'll have Giacomo address this question. Giacomo?
Yeah. Thanks for the question.
The ask by the FDA to move progranulin as co-primary endpoint came as part of the review of the statistical analysis plan that we submitted several weeks ago. We didn't submit any new data to justify this recommended change by the FDA. Previously, in 2024, we discussed the use of progranulin as confirmatory evidence in addition to a single pivotal phase three study, and the FDA had agreed upon. And this is a change that stemmed from this original discussion. But again, no new data were submitted by the company.
All right. Have you previously shown them the correlation between plasma? Because specifically, the co-primary endpoint is plasma progranulin versus CSF.
We hadn't shown the correlation, but we had presented as part of the breakthrough designation package the results on the additional progranulin in plasma and the CSF that were comparable in magnitude. All right.
One question, please, on the Amyloid beta ABC program first in human trial in 2026. I know it's early, but not in clinic yet. But curious to hear how you're thinking about clinical development, sort of leveraging the data generated by approved amyloid beta antibodies and those in development that can cross the blood-brain barrier easily with technology. What would a proof of concept study sort of look like, and what would you like to see to move forward into late-stage programs? Would it be just imaging data or clinical data? And when it comes to safety, there were very low levels of ARIA for Trontinemab. Does that molecule, do you know if that molecule has an active Fc region? And what are your expectations for your amyloid beta ABC? Will that translate the low ARIA rates and safety translate?
Maybe Giacomo can address the first part of the question, particularly in terms of what we believe a proof of concept would be for our anti-amyloid beta ABC. Sure.
The most recent data presented by other companies have shown that using biomarkers such as amyloid PET, it's possible to derive anti-amyloid treatments relatively fast and relatively early in the development program. So the current thinking is to use a similar approach and use essentially biomarkers, amyloid PET, as well as the p-tau species in plasma to have information about the target dose and have an early read on pharmacodynamic effects that are important for therapeutic benefit. Regarding the other question was about what we are expecting to see and will be, we will design studies to provide evidence of very meaningful and fast amyloid clearance, but using both PET biomarkers as well as through biomarkers.
Yeah.
So just to add to this, there's very clear path for anti-A beta drugs now, as Giacomo said. We want to see profound reduction of A beta plaques within three to six months. We want to see minimal ARIA. And Roche is also using a fully effector function. So we don't think that that will impact the ARIA. I think the ARIA is impacted by the way the ABC or the blood-brain shuttle enters the brain. So we expect minimal ARIA, and we also are hoping to see a low level of infusion reaction, something that was not reported with sort of competing antibodies. So we think that there is very clear sort of proof of concept for a drug that can happen with a fairly small clinical trial fairly quickly.
All right. Thank you very much for answering my questions, and I'll hop back into Q.
Thank you.
Our next question comes from the line of Miles Minter with William Blair. Please proceed.
Hey. Thanks, everyone, for taking the questions. The first one on INFRONT 3 again, I know you've only enrolled, I think it's 16 asymptomatic patients in INFRONT 3. It's not part of the primary analysis, but is there a path forward for those asymptomatic patients to get them on label if you do see positive data from INFRONT 3 in the symptomatic cohort? That's the first one. The second, I'm curious as to the comment that the progranulin efficacy on lysosomal function is actually enhanced if it gets uptaken through LRP1 versus sortilin 1. If you could just expand on that, because that is a source of investor concern that you wouldn't actually get active progranulin concentrations in the lysosome itself if you block Sort1. So that's the second one.
And the third one is just coming back to Pete's question. If you're going for fast amyloid removal with your amyloid antibody with the ABC carrier technology, is it safe to say that you'd want to see greater than 91% amyloid clearance at six months that we did see from the Trontinemab data out of AAIC with the high dose? Thanks very much.
Thanks, Miles. Maybe I'll address the first question and then pass it to Arnon to answer your progranulin biology question and to Giacomo on the anti-amyloid beta. In terms of INFRONT-3, as you asked, you're correct, Miles, that we have 16 asymptomatic carriers that we have data on. And as of now, we have not had any direct discussion with the agency in terms of label and what the impact of that data will be.
As I said, we will be doing a sensitivity analysis based on data from these patients, and then depending on what we see, we would have further conversations on the label with the agency. I will pass it to Giacomo to speak about, oh, to Arnon to speak about the progranulin biology question first.
Yes, Miles. So this is a recent publication by an academic lab. Well, sort of they compared actually with sort of gene therapy progranulin that mutated that does not bind Sortilin and progranulin that can bind Sortilin. And they showed that the progranulin in mice that are deficient in endogenous progranulin, and they showed that the progranulin that does not bind Sortilin is actually more potent in multiple aspects. It can reduce neurofilament, whereas the wild-type progranulin was not able to do that. It can reverse multiple lysosomal pathologies more potently than the wild-type progranulin.
It is surprising, but that's what they reported, and I'm happy to send you the publication. That's a second publication from this group showing that progranulin that cannot bind Sortilin can restore both intracellular pathology, primarily, again, lysosomal pathology in microglia and overall disease pathology.
Giacomo, do you want to address the A beta question?
Absolutely. So, Miles, we are very pleased to see the results that Arnon presented about safety of AL037 in the non-human primates, which shows very strong brain penetration. We aim with this program to show evidence of fast and very meaningful reduction of amyloid in the brain along with a safety profile, which is favorable, meaning very low frequency of ARIA, no significant concerns around anemia, and potentially lower number of infusion-related reactions, as well as developing a compound that lends itself to subcutaneous administration as part of the development program.
We don't think that we necessarily need to have a greater efficacy in removing amyloid than 91% that you cited with Trontinemab. Alzheimer's disease is a very large population with very significant unmet needs, and I think we—I mean, these are the goals of the program, not necessarily showing superiority, which I don't think is needed at this stage.
Makes sense. Thanks for the question.
Thank you. Our next question comes from the line of Tom Schrader with BTIG. Please proceed.
Thanks for the very informative session. Just to the last point, shouldn't the Sortilin or progranulin that can't bind Sortilin be more active? It's essentially stabilized. So doesn't it make complete sense?
Yes. In our mind, it does make sense. But as sort of Miles just alluded to, I mean, there is still raging debate in the field whether how essential Sortilin is for the function of progranulin.
And despite the fact that there is a wealth of evidence that progranulin can enter the cells without Sortilin, enter lysosomes, retain functionality both in cell culture and in mouse models in vivo. And despite our phase two data, the open-label data showing that all the parameters sort of go in the right direction: cognition, biomarkers, imaging. So for us, it makes sense. But yes, hopefully, the actual phase three data will convince the doubtful. I get it. I get it. I get it. Okay. And then with all your work in shuttles, you must-or it seems likely you've made either a shuttle direct progranulin or a shuttle Sortilin receptor. Do either of them behave better in the gazillion assays you must be able to run, or do you think 01 and 101 are, for you, going to be good enough forever?
Yes, we are sort of developing second-generation programs for everything that we do. So far, we think that 001 and 101 are looking really good. I mean, the issue with enzyme replacement therapy for progranulin is controlling the dosing. Progranulin is a growth factor. We have a built-in safety feature that we cannot elevate progranulin more than two to threefold, which we think is a sort of safe domain. If you do enzyme replacement therapy, you can elevate progranulin in the periphery way more than that, and that could really lead to adverse effects. So we think that there are safety issues. One of the companies that developed enzyme replacement therapy for progranulin had to sort of show significant immune-related adverse effects and had to use immunosuppressives to deliver the drug.
Our drugs seem to be very well tolerated to the point that we think it will be applicable for prevention therapy if the data justify that. So far, we think that we have a really good drug, but we are always developing second-generation drugs. We think that the target is interesting.
And then the last one on the siRNAs, you gave a relative amount of delivery relative to systemic of 40-fold. But do you know you have enough? You kind of know how much siRNA you need outside of cells in primates or something very close to humans. Do you know you're getting enough siRNA in? And sometimes, are you out of the woods with PK for siRNAs?
Yes. In the blood and all the experiments were done with equal modality with the ICV and peripheral injection.
So we think that we get and we see up to 80% suppression of the SOD mRNA. So we think we are getting enough siRNA to the brain. We are sort of in the midst of sort of non-human primate studies. We'll see how it's translatable. But so far, what we see is that we can get enough siRNA both to peripheral tissues and to the brain.
Okay. Great. Thank you.
Thank you. One moment for our next question. And he comes from the line of Yaron Werber with TD Securities. Please proceed.
Thanks for the great event. This is Steven on for Yaron. A few questions here. So for the anti-amyloid beta ABC program, you mentioned first in human by 2026. And you discussed two molecules, AL037 and AL137, which seems to be new. And you highlighted a few differences in the half-life. So what accounts for those differences?
Are these two different molecules with different epitopes, or is this the same antibody with a different ABC carrier that might affect the PK/PD? And then secondly, just to clarify, are you still deciding between 037 and 137, which look pretty similar? And how would you make the decision of what to take into the clinic?
Arnon.
Yep. Yes. The difference between the two antibodies is the ABC module. I mean, they have different affinity, and the affinity dictates both the sort of level of brain penetration and the pharmacokinetics. So the difference in pharmacokinetics is sort of target-dependent clearance in the periphery. So they have different pharmacokinetics. It's not clear what's the optimal peripheral pharmacokinetics for anti-A beta antibodies. But we think that we have two very, very potent and promising anti-A beta antibodies that are driven by two variants of our ABC.
At this point, we are advancing both of them. And if there will be, we will continue to explore. If there will be data that will clearly point to one of them, we will advance one. But at this point, we think that both of these antibodies are very promising. They have different features that are worth examining. And we are committed to advance both of them at this point.
Understood. And maybe finally, you mentioned an interim data update of Mivysnuvart and progranulin AB in the first half of next year. What can we expect to see from that in terms of patients followed or time of follow-up?
So I can respond to that. The interim analysis planned in the first half of 2026. We haven't actually divulged the exact details of the interim analysis, and we shall be doing that in the future.
Thank you very much.
Thank you so much. One moment for our next question. It comes from Paul Matteis with Stifel. Please proceed.
Hi there. This is Julianne for Paul. Thanks so much for taking our question. I appreciate you hosting this very informative event. Could you just describe, have you ever shared beyond the 12-month data that you've disclosed or INFRONT-2 where you've had 12 patients compared to the 10 patients in the longitudinal FTD registry dataset? And if you have continued to follow patients, is there anything even qualitatively you can share about how these patients are doing or how disease has progressed within them relative to natural history? And then I guess briefly a second question. You talked about 5%-10% of FTD patients having GRN mutations.
If you were to guess on which end of that range do you think most of the evidence actually supports, and how confident would you be in driving patient identification efforts? You talked about misdiagnosis in this patient population. So anything you can talk about that would be great to hear. Thanks so much.
Great. Perhaps, Giacomo, you want to address the first question?
Sure. So as you mentioned, the phase 2 study had 12 patients treated with latozinemab open label, and we had 10 matched controls from GENFI at one year. The sample size is very small, and there are not many data at two years in the registries to support any kind of analysis as we did at one year.
We have looked at biomarkers after two years, and the sample size is small because there are not all the subjects who provide data at one year were available for two-year follow-up. This is a very severely progressive disease. But what I can tell you is that the drug appears to be safe, well-tolerated. The biomarker effect that we saw at two years in a smaller number of subjects is consistent with what we have shown at 48 weeks. And by mid-Q4 this year, we will present the results in a significant number of patients: 103 symptomatic patients treated for 96 weeks. So we think this data will be the one that will be the most informative.
Arnon, do you want to add anything?
Yeah. I can address the - oh, you're - the second question. What's the second question?
You can.
I think the second question was around the FTD range, the 5%-10%. Yes. The prevalence. Chris, would you mind re-asking that question more specifically? Yes. Where it is on the range?
Yeah, so the fact is we don't exactly know. But as Sara showed you, up to 40% of progranulin mutation carriers are misdiagnosed with other types of neurodegeneration. So you think there is a fairly high level of misdiagnosis of progranulin mutation carriers that sort of don't fall into FTD. There was a recent Los Angeles Times article on FTD that sort of put FTD as a very wide range of somewhere between 50 and 250 per 100,000 patients. That's something we think that we are looking at medical sort of claims, and so we will have a much better idea on the prevalence.
I mean, we will disclose at a later stage. But in general, again, as Sara said, that once there is genetic testing available and once there is a drug, I think that the real prevalence will really come out.
That's helpful. Thank you.
Thank you so much. One moment for our next question. It comes from the line of Alec Stranahan with Bank of America. Please proceed.
Hey, guys. Thanks for hosting the R&D call today and for taking our questions. Maybe first on AL137 versus AL037, you mentioned the reduction in reticulocytes between these two assets. Following up on a previous question that was asked, is this also a driver for which asset you'll take forward? And I guess, did reticulocyte levels recover in your preclinical models?
Yeah. In general, safety is a parameter.
What we've shown with Trontinemab is that sort of anemia is less of an issue than was initially thought. It's still, I think, up to 10% of the patients suffer from some level of anemia. In our non-human primates, yes, reticulocytes are very sensitive to both multiple blood draws and to transferrin-dependent drugs. So there was a reduction in reticulocytes, but there was a rapid recovery. And the real measure will be long chronic number of red blood cells and hemoglobin. And so far, we don't see changes in these. But absolutely, the safety will be a component of drug selection.
Okay. That makes sense.
Then I guess, how do you think about 001 and 101 as monoclonal antibodies versus other MOAs such as gene therapies in development for FTD, GRN, and maybe Alzheimer's as well, obviously noting that the others are a bit earlier in development? Thanks. Yes.
Arnon, do you want to?
Yes. I can take this. So as you said, both sort of gene therapy, the small molecules, the enzyme replacement therapy, they are both very early. So we are comparing some hypothetical potential to an actual. We are going to get pivotal phase three data in a few weeks. So it's really hard to compare. But conceptually, sort of the two gene therapy companies are struggling. I mean, one of them could not show sustainable elevation of progranulin. So basically, progranulin was elevated for a few months and then sort of went down.
The second company had sort of significant AAV-related adverse effects and again has to use immunosuppressive drugs and to significantly reduce the dose. So there are technical issues with gene therapy also. And gene therapy still infects a small percentage of the nerve cells. And you assume that this small percentage of nerve cells will be a depot, will produce large amounts of progranulin that will then diffuse throughout the brain for the other brain regions. It's not clear how effective it is. And again, there will be a large disparity between some regions of the brain that have very high level of progranulin, other regions of the brain that have maybe insufficient level of progranulin. It's not going to be a homogeneous distribution. And we offer the correct level of elevation. We offer homogeneous brain distribution. So we think conceptually at least that our drugs could be superior.
So the two gene therapies, again, have safety issues. I think have durability issues. And I think we also could have efficacy issues that didn't really show any benefits outside of, again, transient progranulin elevation. The enzyme replacement therapy is still early. It was on hold for several months because of adverse effects. It's requiring, again, immunosuppressive drugs to deliver it. It's not clear how viable it will be. And again, it will be a big discrepancy between very high level of progranulin in the periphery versus we'll see if sufficient level of progranulin in the brain. And there are also small molecules drugs that try to activate transcription from the progranulin gene. In the past, sort of these small molecules were tested and failed. And there is a small molecule drug that sort of blocks sortilin, does conceptually what we do with an antibody.
And again, it's very early, so you don't really know the off-target activity. Progranulin sortilin is a part of a very large family of sorting receptors with very similar structure. So it's not clear what the off-target risk or adverse effects of a small molecule will be, what the durability will be, and what the ultimate efficacy will be. So we think that at this point, we are in a very different place from competitors, both with how advanced we are and the scientific rationale for the program.
Got it. Thanks, Arnon. I appreciate the color.
Thank you so much. Our next question is from Graig Suvannavejh with Mizuho. Please proceed.
Hey. Good afternoon or good morning, where you guys are. Thanks for taking my questions, and thanks for the presentation. I just wanted to revisit INFRONT-3 real fast just on the co-primary endpoints.
Could you just remind us if you need to hit a p-value that's 0.025, or is there room to hit 0.05 on both? I assume the former, not the latter. And as a follow-up, if you do end up seeing positive data, what are the gating factors in terms of next steps to be able to file a drug? If you could just remind us whether there are any CMC-related issues. Obviously, you'd have to meet with the FDA, but just trying to get a sense of how "quickly" you could actually indeed file for approval. Thanks.
Maybe if Giacomo can address the first question, and I can take the second part.
Sure. So we don't split the alpha. For the trial to be positive, both co-primary endpoints need to be met, and they are tested at the same time, not sequentially.
So both the CDR plus NACC, as well as plasma progranulin, they need to each show a p-value that is p less than 0.05.
Great. I think in terms of just the BLA, etc., if the data are positive, we are already poised to be able to start working on getting the BLA filing going. And we are on track for any of the commercial manufacturing activities to do that in a rapid manner.
Okay. Thank you for the answers to both those questions. And just one last follow-up. With regards to any potential next opportunities with latozinemab, would you think about potential label expansion besides just potentially the asymptomatic patients? I know a long time ago there were interests in other indications as well for AL001.
Giacomo?
We are currently having those discussions both internally and with our partner, GSK.
So this is a very timely topic, and we'll disclose further details at a future date.
Okay. Thank you very much.
Thank you so much. And we have a question coming from the line of Pete Stavropoulos with Cantor Fitzgerald. Please proceed.
Yes. Thank you for taking my follow-up. A question on the scales to be used in phase three. For FRS, is this a more or less sensitive measure compared to CDR and some of the boxes, especially for certain, let's say, where you are within a disease stage, early versus later? Will we be able to see different rates of improvement on FRS versus CDR over the 96 weeks of treatment? And is one better for asymptomatic versus symptomatic? How should we be thinking about that when the data comes?
Giacomo?
Yeah. Great question.
Most of the data that we have around the natural history, natural progression of the disease are the one generated using the CDR plus NAC. The FRS, obviously, it's a scale of interest, is an exploratory endpoint. The sensitivity and rate of progression on the FRS are not very well known or described. Hence the decision to use the CDR as primary outcome measure, which is being validated in FTD as a whole and is the one that is recommended by the FDA. It will be interesting to see the results on the FRS, which is an exploratory outcome measure. We'll also, obviously, as you said, investigate the effect, I mean, the change over time in pre-symptomatic as well as symptomatic subjects and the sensitivity to change over time. It will be an important analysis.
Okay. Thank you for that.
Thank you for taking my follow-up.
Thank you so much. Now I will transition back to Katie Hogan for any webcast questions on the other side. Back to you, Katie.
Great. Thank you. I think we have time for one more question that we received online. This question comes from Sean at Morgan Stanley. Giacomo, this question's for you. What are the key differentiators of latozinemab compared to other therapies in development for frontotemporal dementia due to a GRN gene mutation? How do you see its potential impact on the standard of care? We're specifically talking about Prevail Therapeutics and Passage Bio.
Thank you, Katie. I think Arnon already addressed these questions. But I would like to highlight the fact that there are lots of unknowns around gene therapy. What we know is the safety profile that doesn't look ideal.
One company has reported only transient increase in progranulin levels in blood and in most patients, not all patients, which is very different from what we observe, and then the other point is the rationale that a 50% decrease of progranulin levels is enough to elicit the disease frontotemporal dementia mutation carriers. And with our approach, we are able to restore progranulin levels to normal levels. While it's a little bit more unclear the rationale around the need to elevate several fold higher than the normal levels, then going back to the safety, one company showed increase in NfL that reflects dorsal root ganglia toxicity. Then the other company had immune adverse reaction. So there is quite some safety liability for the use of gene therapy currently, and that pertains around progranulin treatment, but also other forms of gene therapy. Okay.
Thank you, Giacomo.
That's our final question for today. And I'll turn it back over to you.
Thank you so much. And I have no further questions at this time. From this end, I will conclude the conference and thank everyone for participating. And you may now disconnect.