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

Good afternoon, ladies and gentlemen, and welcome to Alector's Conference Call and Webcast Crossing the Blood-Brain Barrier: Developing Alector's Next Generation of Investigation Therapies for Neurodegeneration. [Operator Instructions] 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 event today. Before we begin, we'd like to go over just a couple of reminders. There will be a moderated question-and-answer session following prepared remarks. To submit a written question, please type it on the question-and-answer panel on the webcast. A webcast replay of this event will be available tomorrow after 3:00 p.m. Eastern. You can find it in the Investors section under Events and Presentations on our website, www.alector.com. I'd like to note that during this presentation, we'll be making a number of forward-looking statements, and you can find our forward-looking statement here on this webcast. I also encourage you to see our SEC filings for more information. Turning now to our agenda, joining me on the call are Dr. Arnon Rosenthal, our Chief Executive Officer; and Dr. Peter Heutink, our Chief Scientific Officer. Today, they'll be talking about Alector's leadership in neurodegeneration. Next, Dr. An, Professor and Robert A. Welch Distinguished University Chair in Chemistry and Director of the Texas Therapeutics Institute at UTHealth Houston, will discuss the state of drug delivery across the blood-brain barrier. Following Dr. An's remarks, Alector lead scientist, Dr. Eric Brown and Dr. Maxime Ah Young-Chapon, will talk about Alector brain carrier in more detail, delving into the details about our proprietary blood-brain barrier approach as well as potential applications. Then we'll invite Dr. Heutink back for closing remarks. And finally, our Chief Financial Officer, Dr. Marc Grasso, will join us to moderate the Q&A portion of the discussion. At this time, I'd like to turn it over to Arnon and Peter.

Welcome, everyone. It's really heartwarming to see that hundreds of people registered to our webinar. As you know, for our drugs, we are striving to be both first and best-in-class. So to the best of our knowledge, we are going to be the first to have data for a drug to -- activating drug in Alzheimer's disease by the end of the year. We are also going to be the first one to have Phase III data with a progranulin-elevating drug in front of temporal dementia by around the end of next year. Likewise, we are, to the best of our knowledge, going to be the first one to have a progranulin-elevating drug in Alzheimer's disease around the end of 2026. So as with drugs, we are striving to be both best and first-in-class with our technology we strive to be best-in-class, and our Alector brain carrier platform has been over 5 years in the making. We took the time to understand the certainty of the technology and how to adapt it to different targets. And now we think that we are finally ready. At this time, our blood-brain barrier technology is becoming an integral part of our drug discovery platform. We are using it in conjunction with novel targets, with validated targets you have seen what blood-brain barrier technology you have done to the Roche anti-Abeta antibody, for example, we have, clearly, clinical drugs that work quite well on their own, but they may be even better in conjunction with the blood-brain barrier technology, and we are exploring that. And finally, we are exploring our blood-brain barrier technology in conjunction with nonprotein therapeutics like ASO. What we expect from our technology is to be able to deliver drugs at lower dosing with better brand distribution possibly with the convenience of subcutaneous delivery, we will be able to develop a protein and enzyme replacement drug that is something that was not possible without the technology. And as I mentioned, we will explore on nonprotein modalities. So at this webinar, we are going to focus on the technology, and we'll show you just one example of incorporating the technology into drugs. But in future webinars, we will show examples of the different drug modalities that we are integrating the blood and barrier technology into. And we are not doing everything alone, we are exploring the possibility of partnerships around the technology with different experts. And again, you will hopefully hear about it in the near future. I will now turn the podium to Peter to go into more details in our -- into our research and discovery efforts. Peter?

Thank you, Arnon. So Alector was founded approximately a decade ago with the vision that brought together the fields of human genetics, immunology and neuroscience. And Alector has been pioneering immuno-neurology as a novel therapeutic approach to treat neurodegenerative diseases. Immuno-neurology is deeply eroded into underlying genetics of neurodegenerative diseases and our therapies harness the power of microglia, the brain's immune cells, to counteract neurodegeneration. Our clinical pipeline of immuno-neurology programs includes latozinemab and AL101 that aim to elevate progranulin levels and are being developed in collaboration with GSK. Additionally, we're advancing AL002, our TREM2 activating candidate in partnership with AbbVie. Latozinemab is currently being studied in a pivotal Phase III trial for the treatment of frontal temporal dementia with progranulin mutations, while AL101 and AL002 are being studied in Phase II trials for the treatment of early Alzheimer's disease. Our past research and development defense has centered around our immuno-neurology approach. Today, however, we would like to focus on enhancing the delivery of our therapeutics to the brain using Alector Brain Carrier or ABC, for short, our proprietary versatile blood-brain barrier technology platform. Dr. Arnon and the team will actually go in much more detail. But at a high level, we know that the purpose of the blood-brain barrier is to maintain homeostasis and protect the brain by restricting access to it. From a therapeutic perspective, this actually presents a challenge to effective delivery of therapeutics must cross the BBB for optimal results. Therefore, as a potential solution, we are developing Alector Brain Carrier to enhance brain penetration of therapeutic molecules, potentially optimizing efficacy and safety of critical therapeutics. Employing a first style approach, Alector Brain Carrier utilizes various fragments binding into specific BBB targets, achieving significant increases in brain concentrations across important cell types like neurons and microglia, and enabling customization to align with cargo specificity. Our Alector Brain Carrier technology platform complements our current late-stage portfolio. Grounded in immuno-neurology, our late-stage clinical candidates already demonstrate effective brain penetration and target engagement. But in parallel, Alector Brain Carrier enables the delivery of additional drugs -- additional novel drugs into the CNS, including antibodies as well as protein and enzyme replacement therapies for the treatment of neurodegenerative diseases. This includes novel programs starting, for example, GPNMB and GCase for Parkinson's disease, and you will hear more about GCase later on in this program, but also additional targets, combined with our ABC technology for Alzheimer's disease, ALS and Lewy Body Dementia. We are also exploring the potential to selectively deploy our technology in a fit-for-purpose manner on our next-generation programs. With a portfolio of first-in-class immuno-neurology product candidates, will retain major rights to our latozinemab, AL101 and AL002 programs while holding full ownership of our novel programs combined with our Alector Brain Carrier targeting Parkinson's disease, Alzheimer's disease, ALS and Lewy Body Dementia. Importantly, our IP portfolio across all programs contains more than 60 patent families, which include 100 issued patents and more than 500 pending patent applications directed to more than 20 targets and/or technologies. Alector Brain Carrier marks an exciting step forward in our mission to pioneer effective treatments for neurodegenerative diseases, guided by innovation and driven by a commitment to improving patients' lives. Thank you again for your time today, and I look forward with you -- to speaking with you later in the program, I will now turn it back over to Katie, who will introduce our key opinion leader on the BBB, Dr. An.

Thank you, Peter. With that background, I'm pleased to introduce you to Dr. An. Dr. An is a Professor of Molecular Medicine and the Robert A. Welch Distinguished University Chair in Chemistry and the Director of Texas Therapeutics Institute at UTHealth Houston. He is a trailblazer in the development of antibody-based biologicals to treat cancers, spinal cord injuries as well as Alzheimer's disease. One of his major areas of focus is developing technologies to deliver antibody-based therapies across the blood-brain barrier for the potential treatment of neurodegenerative diseases. He serves as Vice President, Drug Discovery for the university. And in this role, he closely collaborates with the Office of Technology Management to promote drug discovery and therapeutic innovation. With over 200 papers published in peer-reviewed journals and 45 filed patents, Dr. An is committed to improving health through novel interventions. Dr. An, thank you for joining us here today. It's a pleasure to have you, and we look forward to your remarks.

Thank you, Katie. I'm pleased to hear -- to be here today with all of you to discuss the state of drug delivery across the BBB, that's blood-brain barrier. Before I start, I do want to disclose that I'm on scientific boards or have equity interest in Immune-Onc Therapeutics, Incendia Therapeutics and the CrossBridge Bio. I also participate with sponsored research with Merck Research Labs. The brain is a privileged site with highly regulated interfaces that controls movement of substances and cells in and out of your brain. These barriers seek to keep the central nervous system isolated from peripheral toxins and to an extent, the peripheral immune system, while at the same time, ensuring adequate nutrient transport. Examples of these barriers are the meningeal barrier, the blood-CSF, that's the cerebral, spinal cord, spinal fluid barrier, ventricular barrier and of course, the blood-brain barrier. While all these barriers are critical to maintaining homeostasis at a protective base environment where they consider central nervous system drug discovery and delivery, they collectively present unique challenges due to the lack of permeability they create for most of the small molecule drugs and almost all large molecule therapeutics, such as antibodies and protease. So what exactly is the blood-brain barrier or BBB? This barrier is between blood vessels and the brain tissue. The BBB is formed by a monolayer of brain endothelial cells supported by pericytes and astrocytes. Compared to other blood [ endothelial ] barriers, the brain-blood barrier or blood-brain barrier has an exceptionally low rate of non-specific transport at high levels of export hubs, which actively remove potential toxins. This is not to say that the BBB is impermeable. In fact, it actively transport imported nutrients, such as sugars, amino acids and minerals such as [ iron ] through its highly specific transporters. Despite the difficulty of drug delivery across the BBB for treatment of central nervous diseases, the highly vascularized nature of the brain and the BBB present a potential avenue for drug delivery, which is the focus of this webinar today. It is well established that the brain-blood barrier creates low uptake of many therapeutic drugs, including antibodies. For antibodies, in particular, the therapies has a very low but yet a significant rate of penetration across the BBB at about 0.1% to 0.2% of the plasma levels. Due to the low level of brain penetration, it has many associated clinical [ figures ] in central nervous system disease space. Significant effort, both in academia and also in the industry had been made to design therapies that can be delivered across BBB by targeting brain receptors to facilitate their passage to the brain through the blood-brain barrier. Now that we have briefly reviewed the challenges of delivering drugs, particularly large-molecule drugs such as antibodies across the brain-blood barrier, let's take a moment to look at some of the potential BBB delivery technologies. There are 2 dimensions being explored simultaneously and also in parallel. The first are the various routes of administration of the therapies. For that part, drug brain injection that bypasses BBB, intrathecal or spinal cord injection and intraventricular or cerebral ventricle delivery into the CSF or intranasal brain delivery to allow therapeutics to bypass BBB altogether. They are also, the technologies decrease the permeabilities of the BBB crossing, either physically or chemically or a combination to allow higher rates of non-specific transport across the blood-brain barrier. For example, electric or magnetic stimulation, such as ultrasound applied to a skull temporarily opens the brain-blood barrier for drugs to enter the brain without the permanent damage to the BBB. Similarly, chemicals such as the [ hypertonic multi-agent ] mannitol can temporarily open the blood-brain barrier for drugs to enter brain without permanent damage to the BBB. These routes of administration offers [indiscernible] in some applications, but have significant risks and challenges for long-term repeated administration of drugs such as antibodies against chronic neurodegenerative diseases such as Alzheimer's disease. The second category is the delivery vehicles. What class of these vehicles utilizes viral vectors such as AAV9 or AAVrh10, nanoparticles and extracellular vesicles, primarily for delivery of nucleic acid to [ base ] the therapeutics such as gene therapies and [ outsized ] oligonucleotides, which is also one of the focus of [ elector's ] multiple drug modalities. Finally, there is this so-called receptor-mediated transcytosis approach to utilize the receptors on the BBB such as transferrin receptor, TfR, and the amino acid transporter, CD98hc, which will be the focus of this webinar by the Alector scientists today. Before I dive into the transferrin receptor as an example for receptor-mediated transcytosis delivery of drugs across the BBB, I want to take a moment to explain what is exactly our receptor-mediated transcytosis. On the left side of the slide, you can see that it's an illustration of a high-level process, whereby molecules are transported across a cell by binding to specific receptors, which are themselves [ protease ]. As the cell membrane on one side of cell, materials or cells being internalized, transcytosed, across the cell and is released on the other side. Upon reaching the opposite side of the cell, the vesicles continues the receptor, likely the complex, fused with the cell membrane and has released their content into the extracellular space of the other side of the cell. This process is known as a receptor-mediated transcytosis. This process plays critical roles in multiple physiological processes such as the nutrient presumption, immune response and neurotransmitter recycling. The receptor-mediated transcytosis relies upon active transport which, unlike sample diffusion or bulk exocytosis, is highly selective. Only molecules that bind to a specific receptor are transported across the cell. On the right side of the slide, you can see a schematic of the transferrin receptor, short for TfR, which is one of the most-studied receptors for delivery of large molecule drugs, such as antibodies or protease enzymes across the BBB. TfR is a type 2 transmembrane receptor, which binds other transport proteins such as transferrin. And it is highly expressed BBB. Transferrin receptor is a homodimer linked by the sulfur bonds. The extracellular domain of the transferrin receptor consists of 3 domains: the apical domain, the helical domain and the protease-like domain. The transferrin receptor binds to other bonds or [ whole ] transferrin protein through the helical and the protease-like domain. You can imagine for the discovery of cargo for delivery of drugs through the BBB for target TfR, we do want to -- the antibody target the helical or the protease-like domains, otherwise, it could compete with natural ligand bonding as a potential side effect. So leave now with the apical domain, which [ Maxime ] will discuss this with you in great detail. So now let's come back to the right side of the slide. sorry, the left side of the slide, which introduced a bispecific carrier cargo antibody design. The gray arm of the bispecific antibody is the cargo, which is a therapy that you want to be delivered to the brain. The right arm with a bispecific antibody is a carrier, for example, anti-transferrin receptor antibody, which binds to the transferrin receptor expressed on BBB. Upon binding to the transferrin receptor, this bispecific antibody construct is -- cross the BBB, delivered inside the brain. Once inside the brain, the cargo arm of the bispecific antibody engages the disease target. That's in the nutshell how this technology works. So what must be considered in general by designing carriers for effective antibody or protein delivery across the BBB to target, [ cells ] targets. First, we started with the choice of a receptor, with ideal candidates being highly expressed BBB, for example, the transferrin receptor, which is highly expressed on BBB and this equivalent level and [ traffic ] in model species, such as mice, we need to have model systems to evaluate these constructs. Then we come to the antibody engineering. We need to consider modulating epitopes. That's where we design antibodies, where antibody will bind to the receptor. As I mentioned, for the transferrin receptor, we don't want to interfere with a normal ligand binding to receptor. That's the, how do you call it, protease [ lag domain ]. And we can also adjust the affinities of the antibodies [ vital ] receptor. For example, for transferrin receptor, if its affinity is too high, you could trap, internalize the receptor themselves. So we can adjust the affinities of the antibody-targeted receptors as well as the formats of the antibody. For example, we can do a single [ chafe away ], fiber fragment or 4 IgG [ used as ] constructs. All these activities to ensure the lack of competition with the native ligands and the retention of a native function of the receptors. And then, of course, it is imperative that we categorize all these constructs at their functions in vitro and in vivo. Specifically, they must verify brain penetration. We need to quantify brain uptake and confirm with the biological effects as well as potential therapeutic efficacy in the different animal models, including nonhuman primates. So despite the many challenges, which we discussed associated with such a nervous system therapeutic development and the delivery of these drugs, we as researchers, both the academia and the industry, are very excited for the slow but steady progress and advancement in this field. We're looking into the future of our BBB technologies and see the potential for many developments including in vivo BBB models, such as tissues, pharma, human-induced pluripotent stem cells, development of a BBB mathematical models that can predict what's happening in the clinic, exploring where the brain may want to deliver the drugs, leveraging in vitro versus in vivo models, ensuring our study of the animal models can be translated to clinical human study. Last but not least, we need to develop additional novel receptor-mediated transcytosis targets with CNS-restricted expression to reduce potential systemic toxicity. Thank you for your time, and I look forward to addressing questions that you might have at the end of this program. Katie, I'll give it back to you.

Thank you very much, Dr. An. I'm now pleased to introduce my colleague, Dr. Eric Brown, who will discuss Alector Brain Carrier in more detail. Eric, I'll turn it over to you.

Thank you, Katie, and thank you, Dr. An, for your excellent introduction of the blood-brain barrier. So here at Alector, we've worked hard for the last several years, first to build our ABC platform and then to optimize it for a wide variety of therapeutics. ABC is a BBB technology that is designed to enable precise and noninvasive peripheral delivery of therapeutics to the brain. We believe that efficacy and safety are optimized with its modular, and tunable design and we validated it for brain uptake with multiple therapeutic cargoes. One of the main goals is to reduce the dose of a peripheral antibody needed to achieve maximum efficacy, both to widen the therapeutic window and to potentially lower the cost of goods and facilitate subcutaneous delivery. ABC technology is based on the receptor-mediated transcytosis mechanism described by Dr. An earlier, a simplified schematic of which is shown on the right-hand side of this slide. As Dr. An mentioned, we believe that using receptor-mediated transcytosis can allow us to convert the BBB from a barrier into a potential route of entry for drugs into the CNS. Our initial work in the ABC field has focused on two BBB receptors, transferrin receptor and CD98 heavy chain. Both of these receptors are highly expressed on the blood-brain barrier and have been shown to drive significant uptake of cargo into the brain and yet they are differentiated both in their cell type localization and their mechanism of entry. Transferrin receptor, as Dr. An mentioned, is an iron transport receptor, and in our hands, it has been shown to rapidly drive cargo into the endolysosomal system of brain endothelial cells, as shown on the top right of this slide. Meanwhile, CD98 heavy chain is a key member of several important amino acid transport complexes such as LAT 1 and LAT 2. And it tends to drive cargo onto the cell surface of endothelial cells and allow for a much slower route of internalization and delivery across the blood-brain barrier. We think it's key to have ABC shuttles against multiple BBB targets in order to facilitate pairing with a wide variety of cargoes. Our ABC technology has been designed to focus on 3 key strategies. The first is versatility, by which we mean the adaptability for a wide range of cargoes, including antibodies, proteins and potentially even nucleic acids. Second is tunability. Many parts of the ABC molecular are tunable, but one important consideration is affinity for the BBB receptor. And then a third one that is very important to us is translatability. By this, we mean the rapid translation of ABC molecules into validated clinical candidates that can transfer from mouse to nonhuman primate to the human clinical system. Looking in more detail at versatility, we've designed and validated ABC carriers in Fab, scFv and VHh formats and have then paired them with therapeutic cargoes in multiple multi-specific formats, several of which are demonstrated on this slide. This system has been tailored for both antibody and protein cargoes, and you can see examples of each with the center of the slide showing a monovalent brain carrier enabling the delivery of a bivalent antibody cargo, and on the right-hand side of the slide, a format for delivery of a monovalent protein cargo. In terms of tunability, as I mentioned, several aspects of the ABC technology are tunable, such as the valency and efficacy effector function chosen, but one of the most important factors is the affinity to the blood-brain barrier receptor itself. We have validated brain uptake of ABC molecules with over 500 full range of affinities to both transferrin receptor and CD98 heavy chain. Through this work, we've learned that lower affinity ABCs are particularly important in optimizing the efficacy and safety window and are able to deliver sustained delivery of therapeutics into the CNS and are most suitable for cargoes that themselves have relatively slower rates of peripheral clearance such as antibodies. Meanwhile, our work has shown that higher affinity ABCs drive a much more rapid brain uptake at the cost of a hit to the systemic clearance. These high-affinity ABCs tend to be suitable for cargoes that themselves have relatively rapid peripheral clearance, such as enzymes and proteins and where it's most important to drive rapid brain uptake. In terms of translatability, we're looking at 4 key factors to enable translation of research molecules into clinical candidates. First, we developed a high-throughput screening format to enable rapid in vivo screening in human transferrin receptor and human 98 heavy chain-expressing mice. We look to translate our biology by making affinity match panels of mirroring TfR-ABC surrogates for rapid testing and disease model systems. At the same time, we look for translatable safety by making sure we only move forward ABC shuttles that have equivalent affinities to human and cyno-BBB receptors. And finally, throughout the entire process, we conduct rigorous developability assessments to make sure that our ABC shuttles and most importantly, our ABC shuttle-cargo pairings are developable and manufactural therapeutics. We'll begin by looking at our TfR-ABC platform. TfR-ABC is a mature platform that has been used to deliver multiple types of therapeutic cargoes to the brain. While we have ABC shuttle -- TfR-ABC shuttles available across a wide range of affinities, most of the data I'll be showing today is with a low affinity anti-TfR panel, anti-TfR binder designed to facilitate the entry of antibody therapeutics. As you can see on the left-hand side of the slide, even the low affinity anti-TfR scFv drives rapid brain uptake with a nearly 20-fold increase in antibodies seen 24 hours post IV dosing. Because of the low affinity nature of the TfR scFv used in this ABC format, we see sustained delivery into the brain out to 1 week post IV dosing and this is also shown in the serum clearance data on the right-hand side of the slide, where we see a relatively minimal effect on serum clearance of this antibody cargo by the TfR-ABC. Beyond looking at antibody cargoes, obviously it was most important for us to demonstrate the brain uptake of Alector antibody therapeutic cargoes, 2 of which are shown on this slide. As you can see, both Target 2 and Target 3 IgG show an increase of 7- to 15-fold increase in the brain parenchyma. And we think this is very important that in this and all subsequent brain uptake data shown, we're looking at antibody levels on what we call the vessel-depleted brain fraction, which means an antibody that's completed the transcytosis process across the BBB and then been released into the parenchyma. As Dr. An mentioned, some blood-brain barrier-targeting antibodies can, in fact, get stuck in the brain vessels. And even though they might appear to be in the brain, they're not actually reaching the cell types of interest, such as neurons or microglia. Beyond looking at the raw brain uptake numbers, we think it's most striking to look at imaging data that shows the final biodistribution of antibody with the addition of ABC technology. On the left-hand side of the slide, you can see an example of brain uptake of the target 3-IgG without ABC technology, and you can see that the minimal amount of antibody that penetrates the brain is really not deeply penetrating into the neuronal layers of interest but is instead around the outskirts of the brain and around the ventricles. Meanwhile, on the right-hand side of the slide, you can see that Target 3 enabled with TfR technology shows a striking change in the brain biodistribution. One good example of this is looking at the hippocampus, where with Target 3-IgG, the neuronal layer is essentially dark, whereas with Target 3-TfR, you see a bright and precise staining of the neural cell layers. This is driven by both the TfR arm of the molecule getting the drug across the BBB. And then the final biodistribution in the brain is really driven by a combination of binding to the BBB molecule and the cargo of interest. So TfR-ABC, we are happy to say, also shows translatable brain uptake from mice, which the previous data was shown in, into the nonhuman primate system. In this study, we did a 2-dose IV injection into NHPs with 2 different antibody cargoes. On the top in gray, you can see an isotype cargo where you see an increase in brain uptake of 15- to 40-fold across multiple brain regions tested. On the bottom in blue, you can see an increase in brain uptake of 3- to 8-fold in the same brain regions. As with the murine system showed earlier, we also validate in the NHP brain that we're seeing significant wide biodistribution and not focal distribution within the blood vessels on the right-hand side. Beyond looking at brain uptake, which can only be taken at a single time point for animal, we use serial CSF sampling shown on the left-hand side of the slide, to demonstrate that we show enhanced brain uptake up to 2 weeks post IV dosing in the NHP system. Even more strikingly, on the right-hand side of this slide, we can look at biomarker data for the Target 1 system. Target 1-IgG is an elector of proprietary immunomodulatory antibody designed to activate microglia in the brain. On the right-hand side of this slide, we show biomarker data for 1 marker of microglial activation, soluble TREM2. As you can see, the naked IgG without TfR technology shows a very modest PD effect, which has enhanced 300- to 400-fold -- 300% to 400% upon addition of the TfR-ABC technology. This data actually matches with prior studies done with Target 1-IgG at 4 or 12x higher doses than was done in this study, enabling the potential to lower the peripheral dose needed in order to achieve maximum efficacy. Importantly, in the same study, we also looked for safety phenotypes such as the well-understood anemia phenotype often seen with TfR-binding antibodies. Throughout the 2-dose duration of the study, we saw no impact on markers of anemia such as red blood cell counts or hemoglobin. We also looked more deeply at reticulocyte levels. So reticulocytes are immature red blood cells that express very high levels of transferrin receptor and which are often killed upon addition of anti-TfR therapeutics. Interestingly, we saw no reduction in reticulocytes after the first administration of any of the test articles. But we did see decreases in reticulocytes in some of the animals after the second dose with some of our TfR-binding antibodies. So this is a very important property that we're evaluating in all further TfR-ABC studies as it's modulateable with many of the trends -- with many of the tunable properties of ABC such as valency effector function and obviously, affinity to the TfR receptor. Beyond looking at brain uptake and safety, we're also obviously interested in making sure that all of our molecules have favorable manufacturability profiles. We took the same Target 3-TfR-IgG shown in a previous slide in set it with a rigorous developability assessment. We look both at high concentration stability, multiple stress conditions and also multiple measures of self-interaction, to show that this molecule has a strong potential for therapeutic administration. Importantly, we were able to increase the concentration up to 150 mg per ml without any impact on product quality, indicating a potential for subcutaneous dosing. While most of the data I've shown so far has been with a low affinity anti-TfR-ABC to facilitate antibody transport, we've also validated brain uptake for a wide variety of human and cyno affinity-matched shuttles in order to facilitate transport of cargoes with a wide variety of mechanism of action. Importantly, we've also validated affinity-matched surrogate panels to enable us to test cargo ABC pairings in different model disease systems. And we've validated binders in both scFv and Fab format at relatively similar affinities in order to match all the different formats we discussed earlier. Moving beyond TfR, we'll next take a look at our CD98-ABC platform. CD98-ABC is not as mature as TfR-ABC, but we're seeing exciting differences in the kinetics of brain uptake and safety profiles that make us think it's a highly orthogonal platform that will allow us to better pair with diverse cargoes that may not be amenable to TfR-ABC transport, such as those that require bivalent formats or that require active effector function Fc. So to look back at some of our initial screening data, we screened across multiple antibody formats and showed several sequence families with strong increases in brain uptake. This data is shown from 1 sequence family in our high-throughput screening format, where we can see an increase in up to eightfold increase in antibody level in the vessel-depleted brain fraction 48 hours post IV dosing. Next, we took some of the shuttles and applied them to a more final therapeutic format, where we see even more striking increases in brain uptake. As you can see on the left-hand side of the slide, even 24 hours post dosing, we see a 10-fold increase in brain uptake in the hCD98 heavy chain-ABC knock-in mice model system. This brain uptake actually increases substantially 4 and 7 days, peaking at over 20-fold over the format-matched isotype antibody. And as you can see, the increase in brain uptake is sustained well past 2 weeks past IV administration. As with the TfR system, we also use imaging data to confirm the final biodistribution of our antibodies. As you can see on the right-hand side of the slide, the CD98 heavy chain-ABC, in this case, with an isotype control Fab cargo shows widespread baring biodistribution. Without an active cargo, we don't see as striking a subcellular localization as with the TfR-ABC. But again, you can see that the crossing across the blood-brain barrier is complete in all brain regions assessed. If we look at some of the differences between CD98-ABC and TfR-ABC, we can easily see the potential to pair with different types of cargoes. As you can see on the left-hand side of the slide, TfR-ABC shows a high Cmax at a relatively short time frame, 1 to 2 days post IV injection, and this can be even further enhanced with higher affinity TfR-ABC. Meanwhile, on the right-hand side of the slide, you see the potential for sustained brain uptake with CD98 heavy chain-ABC, which, as I said, has both high initial brain uptake but even further increases 1 to 2 weeks post dosing. And again, just to note, all of this data is with an Isotype-controlled cargo and the final brain biodistribution and brain uptake patterns are going to be cargo-dependent. We also wanted to look at initial safety data for our CD98-ABC panel. So on the left-hand side of the slide, as Dr. An mentioned earlier, one key consideration for ABC or any BBB shuttle is that they not interfere with native functions of their receptor. So obviously, one of the main functions of CD98 heavy chain is its role in amino acid uptake. So we took care to screen our CD98-ABC molecules to ensure that any that we move forward do not decrease amino acid uptake after induction on human cells. So on the left-hand side of the slide, you can see brain uptake -- or amino acid uptake data, which is, in particular, uptake of leucine through the LAT1 complex. On the right-hand side of the slide, you can see some of our initial in vivo safety data. So we thought it was important to measure changes in hematological parameters. CD98 heavy chain is expressed on many cell types within the hematopoietic system. We saw no notable changes in anemia markers such as red blood cell counts, which are shown here or hemoglobin for 2 weeks post IV injection. And importantly, we also saw no major immunological changes in immune cell-type populations, which is also a key consideration. So beyond isotype-controlled cargo, we've now paired CD98-ABC with multiple electrotherapeutic cargoes. On this slide, you can see in the middle, Target 2-IgG for which additional CD98-ABC technology facilitates a ninefold increase in brain uptake 72 hours post IV dosing. And you can see Target 4-IgG for which addition of the CD98-ABC technology increases brand uptake by tenfold, again in the murine model system. And as with our TfR-ABC system, we've worked hard to validate that these target CD98 heavy chain pairings are developable therapeutics. And so this is some initial manufacturability data indicating that both Target 2, Target 3 and Target 4, all of which are proprietary elector antibodies pair well with the CD98-ABC system and are viable as therapeutic candidates. Like with the TfR example, we've been working to validate CD98 heavy chain binders across a wide range of affinities. We've seen validated brain uptake for binders with single-digit up to around 500 nanomolar binding to CD98 heavy chain. And here, we're showing data for one particular very well characterized antibody family. As you can see, as with TfR-ABC, we only move forward molecules that have highly matched affinities between human CD98 and cyno CD98 receptors. Interestingly, there's a mechanistic difference where we don't see a brain uptake with the load of very low affinity, anti-CD98-ABCs as we did with anti-TfR, and we think this is really due to the differentiated mechanism of brain uptake seen with these 2 receptors. So I know I've gone through a lot of data pretty fast. So I just wanted to highlight some of the key strengths and the current status of our ABC platform. We validated brain uptake in multiple different formats with multiple types of ABC binders for both TfR and CD98-ABC across relatively wide affinity ranges. Our ABC platform, because it does not require any engineering in the antibody Fc itself, is thus compatible with any sort of Fc engineering, looking at either effector function or half-life extension. We've generated matched human/cyno affinity panels for both TfR- and CD98-ABC and generated matched marines surrogate panels for TfR-ABC, which is currently at work in progress for CD98-ABC. In terms of brain uptake, we've shown high absolute [ levels in ] fold, increased levels in NHP and mice brain for TfR-ABC and in the mouse brain for CD98-ABC. In terms of application to electric programs, we've demonstrated increase in brain uptake with 5 cargoes for TfR-ABC and 3 for CD98-ABC with multiple other programs ongoing, and both have been shown to pair well with protein cargoes in certain applications, one example of which will be shown in the next section of this deck. Thank you, Katie. I will turn the deck back over to you.

Thank you very much, Eric. At this time, I am pleased to introduce Dr. Maxime Ah Young-Chapon, one of our lead scientists who will talk more about the potential applications of our ABC platform. Maxime?

Thank you, Katie. It's my pleasure to present how Alector is applying our ABC platform for protein replacement therapies in neurodegeneration. Today, we're specifically focusing on our brain-penetrant GCase enzyme replacement therapy for the treatment of Parkinson's disease. I'll start by describing the genetic rationale for targeting GCase. Mutations in GBA1 are some of the most common genetic risk factors for Parkinson's disease and Lewy Body Dementia. Up to 15% of Parkinson's disease patients and up to 30% of Lewy Body Dementia patients carry mutations in GBA1. Based on these statistics, we estimate about 1 million GBA1 mutation carriers for each of these patients' populations worldwide. We also note that individuals that carry 2 mutations in GBA1, so 2 mutated copies of the GBA1 gene are affected with the lysosomal storage disorder, Gaucher disease. Though the most common subtype, Gaucher Type 1, does not present with neurologic symptoms, these patients also have increased risk of developing Parkinson's. In the next slide, I'll describe the function of this disease-modulating gene. The GBA1 gene encodes the lysosomal enzyme, glucocerebrosidase or GCase. This enzyme catalyzes the hydrolysis of its substrates, glucosylceramide and glucosesylsphingosine into their lipid and sugar components. When mutations reduce GCase activity, you have an increase in toxic accumulation of these substrates. We believe this substrate accumulation contributes to the increased risk and accelerated progression of Parkinson's disease observed in GBA1 mutation carriers. Our goal is to restore GCase activity by providing brain-penetrant enzyme replacement therapy to reduce substrate levels back to normal. Importantly, we believe that rescuing GCase activity directly will be more efficient at reducing glucosylphingosine than glucosylceramide substrate inhibition. Observational studies published in the last few years support the hypothesis that GCase activity and substrate accumulation are linked to Parkinson's disease progression. The figure on the left demonstrates that patients with lower GCase activity in the CSF at time of diagnosis tended to decline faster in their cognitive scores than patients with the highest GCase activity in yellow. The figure on the right shows the stratification of patients based on their ratio of glucosylceramide levels to sphingomyelin in the CSF. The red line shows patients with the highest baseline glucosylceramide to sphingomyelin ratio. That is to say these are the patients with higher relative glucosylceramide levels. And these patients progress faster than patients with lower glucosylceramide levels in blue. Together, these data support the hypothesis that reduced GCase activity and increased lipid substrate levels contribute to the faster clinical progression of Parkinson's disease in GBA1 mutation carriers. Parkinson's disease is a chronic progressive neurodegenerative disease. Its symptoms can be categorized into motor and non-motor impairments. Approximately 90,000 Americans are diagnosed with PD each year, and no disease-modifying treatment is approved to slow progression of PD. There is a strong genetic component to Parkinson's disease with 10% of PD being familial and as mentioned before, 5% to 15% of patients carry mutations in GBA1. Our solution for patients that carry GBA1 mutations is a brain-penetrant enzyme replacement therapy. Our therapeutic is composed of 3 moieties, an engineered enzyme optimized for expression, stability and activity, an Fc fragment to enhance serum half-life of GCase and an ABC moiety to facilitate brain penetration. The versatility of the ABC platform allowed us to test several protein formats for optimal expression and stability. The tunability of the platform allowed us to optimize the ABC target and antibody affinity for maximum tissue and cell delivery. And finally, availability of affinity-matched anti-mouse surrogate molecules allows us to test our candidates in commercially available genetically engineered murine models. Now I'd like to share some data that were generated in this program. GCase exerts its function in the lysosomes of cells. As such, it's important that our therapeutic to be able to traffic to that comportment for optimal activity. In the experiment on the left, we treated human neuroblastoma cells with GCase ABC overnight. We then stained those cells for the early endosomal marker, EEA-1 and the lysosomal marker LAMP-1. As you can see on the top left panel in the overlay, there's a significant portion of the GCase ABC signal in green that overlaps with the lysosomal signal in purple and that overlap is shown in line -- in white, demonstrating the ability of GCase ABC to traffic to this organelle. On the right, we used a GCase-activated foreseen substrate to measure enzymatic activity in cells. The non-fluorescent substrate is conjugated to glucose, GCase catalyzes the removal of this glucose moiety, which allows this substrate to fluoresce and we measure this signal by flow cytometry. Our goal is to restore the GCase activity in brain cells to reduce substrate levels back to normal. What the data on the right is showing you is that our GCase-ABC protein was able to restore GCase activity in GBA1 knockout human neuroblastoma lines had concentrations below 5 nanomolar, which is compatible with intravenous delivery. In contrast, recombinant GCase without ABC in black was not able to fully rescue GCase activity to wild-type levels, as shown with the dotted line. As Eric presented earlier, our ABC platform encompasses a range of ABC affinities. We, therefore, tested the effect of varying the target affinity of our ABC moiety on the rescue of GCase activity. What we found was that as the affinity to ABC increase, the concentration required to achieve full rescue of mouse neuroblastoma cells was reduced. And this relationship between ABC affinity and concentration required for rescue of GBA knockout cells is shown on the right panel. This data showcases a range of affinities that are compatible for our therapeutic hypothesis and allowed us to explore different affinities in vivo. Our mouse in vivo results show that higher ABC affinity was associated with faster clearance as shown on the left panel through serum concentration at different time points after injection. Concurrently, the level of brain uptake measured as GCase activity in the vessel depleted fraction was the highest with medium affinities with up to 44% increase in GCase activity over controls. In summary, we believe that GBA1 mutation-carrying patients may benefit from enzyme replacement therapy to halt or slow down progression of Parkinson's disease. The data I've shared with you shows that our ABC platform allows recombinant GCase to rescue glucocerebrosidase activity in GBA knockout cell lines. And the tunability of our ABC platform allowed us to experimentally determine the optimal balance between cell rescue and brain parenchymal delivery to achieve over 40% increase in GCase activity in the brain of wild-type mice. I hope this data was a good showcase of the vast potential and application for our ABC technology platform. I'd like to thank you all for your attention. And I will now turn it back to Peter.

Thank you, Maxime. So in summary, Alector is in a leadership position in the fast-evolving field we term immuno-neurology which lies really at the intersection of genetics, immunology and neurology. Our ambitious goal is to deliver multiple transformative therapies to patients years ahead of others. We seek to do this not only through the development of novel therapies, which harness the innate immune system to address major unmet needs in neurodegenerative disease, but in parallel through the delivery of these therapies via Alector Brain Carrier. We believe our proprietary versatile blood-brain barrier technology platform has the potential to move us into the next area of CNS solutions for millions of patients and their loved ones desperately in need of progress. We are dedicated to advancing the development of our ABC technology, which currently encompasses antibodies as well as protein enzyme-replacement therapies aimed at potentially treating neurodegenerative diseases such as Alzheimer's disease, ALS, Parkinson's disease and Lewy Body Dementia. You have seen that the modular nature of ABC allows the affinity, valency and format of the final therapeutic to be harmonized with the mechanism of action and cell type specificity of the associated cargo. Our technology's adaptability is demonstrated to the versatile bispecific formats, complemented by customizable Fc adaptations for optimized effector function, half-life and single chain configurations. Based on the translatability of preclinical safety and efficacy studies, our technology appears to exhibit a favorable safety profile. And overall, our potential first-in-class clinical stage assets, our proprietary ABC technology platform, our experienced team and world-class partners positions us well today and serve as catalyst for our future growth and success. Marc, we are now ready to begin the Q&A portion of our program.

Thank you, Peter. We have a good number of folks in the queue for questions. So operator, if you'd like to advance to our first question.

[Operator Instructions] Our first question will come from the line of Pete Stavropoulos from Cantor Fitzgerald.

Thank you for hosting this event. Very informative. Exciting to see more details about the platform. For Dr. An or Dr. Brown, could you just give us a little bit more color around how you're thinking about affinity of the brain carriers, either CD98 or transferrin receptor for optimal delivery? And will the affinity need to be tuned for delivery of various modalities? And in terms of delivery, is there enrichment in different parts of the brain when you use different affinities for either of the two, CD98 or transferrin receptor? And if so, how can you leverage these properties for -- across various diseases?

Thanks, Pete. Dr. An, any high-level comments and maybe, Eric, you could comment more specifically for our efforts?

Yes. That's actually a very good question. So as Peter said in his remarks that for targeted transferrin receptor or the CD98 heavy chain are the future receptors. So we want to design fit-for-purpose delivery vehicles. That is actually -- you precisely that where we want to deliver drug to the brain so the affinities can be [ toured ], of course, based on in vitro and in vivo validation. And so the idea that is for every drug molecule we design, we want to select the best affinity and also because modulators format, [ verified ] in fact as well as Fc engineering. So in summary, yes, I think the Alector platform is a collection of multiple antibodies targeting these receptors. You can pick/choose that designs -- select the best molecule for the specific drug you want design.

As Dr. An mentioned, this is a large part of the reason why we designed such a modular format with such a wide range of binders because we've already seen with different classes of cargoes that we really do require some changing of the affinity. And this is due to a lot of different properties, brain uptake, making sure the drug doesn't get stuck in the blood vessels and then also ensuring peripheral safety, right? So lower affinity you can get away with often helps with some of the measures of safety, such as the anemia phenotype mentioned or potential degradation of either TfR, CD98 heavy chain receptor. So this is why we have a suite of binders that any time a new target comes up, we really try to apply multiple affinity binders against both targets and then screen both in vitro and in vivo to make sure that we have the optimal pairing. It's definitely not a one-size-fits-all approach.

[ And Eric, ] in terms of different affinities, enrichment in different parts of the brain or is it uniform?

Yes. So that's an interesting question. I mean what we've seen across multiple cargoes is that at least for TfR and CD98 heavy chain, we see relatively broad biodistribution in different brain regions. Now what might actually have more of an impact on the final distribution is the cargo itself, right? So as you saw in that Target 3 example, Target 3 is itself expressed on neurons and microglia. I mean you could see a very striking staining of, for example, that neuronal layer in the hippocampus. But that wasn't just due to the TfR technology. That was due to a combination of both TfR and Target 3 binding.

Got it. And for the GBA1, the GCase program. On the pipeline slide, I see Parkinson's, I see LBD. However, I do not see Gaucher. Can you just help me understand the rationale for going after Parkinson's and LBD and excluding Gaucher, if that's the case, which to me, at least at the surface, seems like the easiest population to show efficacy in and perhaps the fastest path forward?

Yes. Maxime or Peter, do you want to comment there?

You want to start Maxime or shall I?

Yes. So I think we reviewed, of course, the Parkinson's, LBD and Gaucher and decided to focus on Parkinson's disease. We feel that while you can see a signal activity in Gaucher patients because the disease is mostly peripheral, it's unclear whether this would necessarily be informative as to potential efficacy in Parkinson's disease. So at this point, we have decided to focus directly on the largest population.

Our next question come from the line of Jeff Hung from Morgan Stanley.

You showed data with significant uptake of cargoes in mice by 7- to 15-fold per TfR. and 7- to 10-fold for CD98hc. What is the optimal increase in uptake of cargo that you look for? And is there a minimal increase or a point where it can be too great? And then I have a follow-up.

Yes. Thanks, Jeff. Eric, do you want to start there?

Yes, I'll take that one. I mean just to note, we have seen increases of up to 20-fold in the murine system for both TfR and CD98 at the Cmax. I wouldn't say there's necessarily a highest level of brain uptake. What we see is that the greater full change we see, then the more we could decrease the peripheral dose and still get that maximum efficacious dose into the brain. So we really -- I mean as high as we can go, as low as we can drive the peripheral dose level, we think will give us significant safety advantages like was seen in the Roche example with trontinemab.

Great. And then currently, your preclinical programs are 100% owned by Alector. How are you thinking about the partnership strategy for these programs? And do you plan to partner these programs like your [ bid ] lead programs? Or are there specific programs that you want to keep wholly owned?

Thanks, Jeff. Maybe I'll start there and Arnon, please add. So yes, you're right, Jeff. These are proprietary programs, and we're advancing them on our own, and we have disclosed programs like GCase and undisclosed programs. I will say that we do have interest from pharma, and we have to balance that as we look at advancing these programs. I can say, thankfully, we're in a financial position where we can advance these on our own for some time and through value-creating events. But at the same time, for the right situations, it may make sense to consider partnerships as well, and we are in discussions there. Arnon, anything else you would add there?

Yes. Basically, our ultimate goal is to have fully owned drugs. But if there are great opportunities to partner the same way we partnered our TREM2 asset and progranulin assets, we will absolutely explore that. I mean we have a very sort of a broad pipeline, and we rather have a drug-developing partnership rather than not be able to develop it because of limited resources. But as Marc said, at this point, we have enough resources to develop these programs on our own and we'll keep doing that.

And our next question comes from the line of Alec Stranahan from Bank of America.

Just 2 quick ones for me. Pretty encouraging preclinical data, especially on the PK side, I guess, as you move your ABCs closer to the clinic, how do you plan to optimize? Or how are you thinking about testing dose and dosing frequency in Phase I studies? And maybe as a follow-up, how translatable would you say the nonhuman primate data is in terms of understanding PK and safety either in terms of the blood-brain barrier composition permeability or normal tissue expression?

Yes. Thanks, Alex. Good questions. Maybe Eric, do you want to start there? And Peter and Arnon can add if appropriate.

So I mean, obviously, we plan to do dose range finding studies in nonhuman primates to rigorously evaluate these parameters. I would say, I mean, there's always some translatability gap as you go into the clinic, and we're doing the best we can to minimize this by, as I said, mapping out expression profiles in these model systems. As well as making sure we're always working with affinity match surrogates. So both in terms of Kd but also kon, koff characteristics between the human and the cyno receptors. So on the engineering side, that's kind of the best we can do. And the PK folks, obviously will have a lot more to say on that.

Yes. In human, for each of our drugs, we have a pharmacodynamic biomarker for progranulin-effecting drugs. We wanted to retain a high level of progranulin throughout the treatment. And this was what determined the dosing level and dosing regimen for our TREM2-activating drug. We had 3 different biomarkers downstream of the TREM2 activation that we wanted to retain active or active intermittently. So the pharmacodynamic biomarker will determine the dosing and dosing frequency with our blood-brain barrier technology, initially in nonhuman primate and then in human.

Thanks, Alec. Maybe just moving to the chat. I see Yaron had a question. Is there anything specific to the ABC technology that would prevent conjugation with other modalities in the future, like ASOs, RNAi, et cetera? Maybe, Arnon or Peter, if you want to comment there.

Yes. I mean we think that the platform is fully suitable to couple a wide range of different molecules. And so this is something that we are actively investigating. We started with antibodies. This was how the platform was originally developed. We realized the potential to use protein and science as possible cargoes. And similarly, we think that ASOs or even small molecules would be feasible. And we are exploring these possibilities, and we hope to report on some of them in other events.

Our next question will come from the line of Carter Gould from Barclays.

This is Leon Wang on for Carter Gould. I have a question on the receptors. I know in your conference, you mentioned that the TFT receptors are expressed in reticulocytes, but I was just wondering where might these receptors be expressed elsewhere in the body? Is there like a specific concentration anywhere else notable that you can mention? And also does these receptors kind of vary either as a person age and also in different disease states?

Eric, do you want to start there?

I will take this one. So I will say, I mean, none of these receptors are perfectly only at the blood-brain barrier. So transferrin receptor highly expressed on reticulocytes and it is expressed in endothelial cells at a lower level in several other peripheral organs such as the liver. CD98 heavy chain is also expressed in some other peripheral organs, off the top of my head, I can think of the spleen, the kidney. So these are things that we are kind of evaluating in both murine and in NHP studies to make sure that we're not seeing any undue effects there, particularly with CD98 heavy chain on immune cells because that's one of its functions beyond amino acid uptake is also mediating integrin signaling, which is important for B and T cell maturation. So we're trying to keep an eye on all of these potential phenotypes. I may have forgotten the second half of your question.

No problem. I was just wondering how -- essentially, what's the variability between one and I guess...

So we had our bioinformatics team take a look at this, most especially in disease settings, right? So when we were evaluating BBB receptors several years back to see which would be the most suitable we only pick those that did not have substantial decrease, particularly in neurological diseases such as Alzheimer's, because obviously, I mean that, at the time, was our largest potential patient population. So we wanted to make sure that these receptors aren't down-regulated in the disease state. In many cases, they're actually -- they can be up-regulated because the diseased brain has changes in the homeostasis that actually make it more activated.

Our next question comes from the line of Tom Shrader from BTIG.

You've mentioned several times about getting proteins stuck in vessels. Can you drive something that looks like ARIA? Is that -- are we going to have to think about that for some payloads?

Those are almost 2 separate questions. So definitely, it's been demonstrated both in the past and in our internal data that both higher affinity anti-TfR-ABCs, but also sometimes specific cargo-ABC pairings can cause the antibody or the protein perching cargo to get mislocalized into the endolysosomal system and not release on the other side, which is where we really wanted to get to in the parenchyma. In terms of driving ARIA, I think that is really more cargo-specific phenomenon. I'm not sure if that has as much to do with getting antibody stuck inside, like in the vesicle portion of the cell. It might be a little bit more related to antibody accumulating on the outside of the cell where there's presence of peripheral amyloid deposits. But I think that's a very cargo-dependent question.

I had a broad follow-up for Dr. An. So much of CNS disease is transmembrane proteins. Is gene therapy the only way to get at that? Or on your sort of playbook are some things that you might -- vesicles or something where you might be able to get transmembrane proteins in, just kind of as a view to the future?

Yes. Actually transmembrane proteins you need [ intracellular ] targets. If the [ expresser cell ] those receptors, they produce good antibody targets. Antibodies do not get use of the cell very well. So if for targets that is intracellular used of a cell, so gene therapy will be a better option. So as Eric has showed that this is -- the drug such that we talked about today has 2 parts. One is the cargo that could be antibody-targeting intracellular proteins or could be a small molecule that can target intracellular targets or gene therapy as it also target intracellular proteins. It is a delivery vehicle that could be antibody targeting transferrin receptor or CD98 heavy chain or maybe in the future antibody targeting different receptors. So recently, as you all know, antibody can link to drugs called antibody-drug conjugates. In fact, the antibodies today can conjugate with a linker, either small molecules, [ at the size of ] oligonucleotides, this for gene therapies for [indiscernible] and also other proteins coupled with this BBB crossing capability. So you can really open up multiple avenues targeting different targets, including actually recently people started looking for antibodies also similar to PROTAC, where you have antibody degraders that these modalities can also be delivered across the BBB to target neurodegenerative diseases. Of course, our lab does not work at this, but for brain tumor, which also suffers as drugs that cannot get use in the brain, can also benefit from BBB-crossing technologies.

Our next question will come from the line of Myles Minter from William Blair.

Maybe for Dr. An and maybe the Alector team can comment on it as well. Just the anemia signals that we're seeing clinically with transferrin receptor conflict [ of theory ]. I think your peers in Denali certainly had an issue there. And even if you look at the trontinemab data for the anti-amyloid antibody from Roche showed there was a potential anemia signal in that self-subsided. So is that something that's inherent to TfR sort of shuttling mechanisms that we're using across the blood-brain barrier here? Or is that more something to do with like the Fc region or the expected regions or the payloads of the drugs, and this can be engineered out? I know you're looking at this potential signal across your platform. I'm just wondering whether it's inherent to TfR? And if you do see that signal, you're going to have to go elsewhere with another shuttling mechanism?

Yes. I think anemia signal is actually mostly related to TfR because the target is intercellular cells. So the TfR as a delivery vehicle has been tested in the clinic. You mentioned Denali, also Genentech and Roche initially. So the safety is the question. There was already a question about the safety issue. So to me, let's say, you desire a chronic drug for chronic neurodegeneration, like Alzheimer's disease. Ideally, you want to have a drug that can be administered subcutaneously, say 1 ml of injection. And so there, you want to find the safety window that's is not going to cause anemia, the transferrin receptor internalization because of the high affinity of your vehicle or the avidity effect on your vehicle. So that's why I think Alector's approach of -- to identify -- you make available multiple affinities, antibodies targeting transferrin receptor. The value based on the clinical dosing strategy to find the best affinity, either lower or higher. You have the intended delivery say, maybe [ 5 or 4 drug ] penetration. But yet, you do not have the side effect such as a anemia signal. So I think it is a fit for purpose, I like the word fit for purpose where you -- for a particular drug design, you need to have a specific vehicle that is appropriate affinity, avidity and also the format such as single chain, IgG or Fab fragment.

Thanks, Dr. An. Eric, or maybe Arnon, anything to add to that?

Just to add little bit to that, I mean, I think the anemia phenotype is an inherent risk in TfR therapeutics, but it's not an inherent outcome. I mean we showed data from a study using modulated effector function Fc where we didn't see an anemia phenotype. We've conducted other studies with maybe more active Fcs and we see that's one of the more key routes by which you can tune the anemia phenotype. We also think that there are some inherent pairings where even with effectorless Fc, you might be able to drive the anemia genotype by physically associating immune cells with the reticulocytes through co-engagement. So this is, I think, one of the most important reasons why we need to have ABC technology against multiple receptors at multiple different affinity ranges because we've seen, even in our hands, much less the clinical data that we can modulate these properties but it really comes out of the mechanism of action of the cargo, right? Like if the cargo is going to require active effector function, we're going to have some risk of anemia as was seen with trontinemab, right? That's a active effector function to drive depletion of an A-beta plaques and it's kind of a little bit inherent in that specific case. So yes, flexibility, I think, is the key.

Yes. I would also want to add that this vehicle, targeted TfR or CD98 heavy chain, maybe future vehicles, as this is very similar to a drug target, you're looking for the drug has efficacy but will use safety window. This is same to say this vehicle also has a safety window. You want to identify the affinity of dosing or avidity of format. This combination of all these that vehicle should be safe, like Eric said, it should not say anemia signal. If that's the case, you need to redesign your drug molecule.

Just a quick follow-up on the GBA1 program. Sorry, just a quick one. Are you using a degradable or ionizable linker for that GCase molecule? Or when it's actually in the lysosome are we expecting the full antibody scaffold to be there with also the active enzyme?

Yes. Maxime, do you have anything to comment?

Yes. So this is fusion protein. There's no degradable linker. The whole construct gets taken up by the cell and is active in the cell.

Our next question will come from the line of Paul Matteis from Stifel.

This is James on for Paul. And actually, I have kind of a follow-up one to Myles' question there. And you kind of sort of answered it. But just wondering, you noted that preclinically in NHPs, you haven't seen any sort of anemia with your TfR1 program. So just kind of wondering how derisking is that as it relates to kind of going into the clinic? And what have we learned from these other programs in terms of how much safety can be derisked here? And then just kind of separately, I'm sorry if I missed this, but just kind of curious where timeline stand today for some of these lead programs and when we can expect more updates?

Maybe, Eric, do you want to start on the first part, then I can pick up on timelines?

Yes. I mean in terms of translatable safety, that was a favorable initial safety outcome that particular molecule hasn't progressed to like a GLP tox study, which is where we would really expect to fully map out the safety risks. So I will say that we are still currently evaluating the safety on a program-by-program basis when we apply the ABC technology, and then we map it out in a TRF study, GLP tox study to make sure we have the most data we can before going into the clinic. But for the timing, I will go to Peter.

Thanks, Eric. I think for the GCase program that we just discussed. We are starting to basically plan out our nonhuman primate studies and to move towards our lead molecule. So that's where we stand at this moment. And we will be happy to update you when we get further down the line.

Yes. We're also advancing a number of undisclosed programs as well. We'll keep you updated, James, I know that's not too satisfying right now, but things are progressing in a fairly broad manner.

Our next question come from the line of Ananda Ghosh from H.C. Wainwright.

I have a couple of questions. The first one is with respect to the anemia data, what's the rationale when you see some aspect of anemia coming back with the second dosing and not with the first dosing?

Eric, do you want to start there?

Yes, that was kind of a surprising phenotype that we saw there. I mean one potential consideration, considering we had 2 dosing events, 28 days apart with a human Fc is that we might have started to develop some ARIA between the first and second dose -- sorry not ARIA, we might have developed some anti-drug antibody between the first and second dose that might have enhanced some of the effector function of the antibody after the second dose. But we have not fully mapped that out. We were surprised to see differences between the first and second dose.

Got it. You mentioned ARIA. When you look at the trontinemab data from Roche, they hardly see any ARIA with their blood-brain barrier platform. And so -- and if we think, looking at your TREM2 program. So first of all, why does it mechanistically makes sense using a transport like ABC kind of transport platform where you don't see such a drastic ARIA, which we will see a normal kind of infusion system?

Yes. Maybe, Eric, if you want to start and Arnon, if you want to comment as well.

I mean I think there's 2 effects in the specific trontinemab example: one, they were enabling themselves to use significantly lower dose by adding the anti-TfR technology on; and the second is by shuttling the drug out of the serum, where the ARIA effect might well be due to perivascular macrophages on amyloid deposits that aren't even in the CNS at all, right? So the drug level in the serum might be what's the most important in driving that. And by lowering the dose and actually increasing the systemic clearance to TfR, both of those mechanisms might decrease the drug level that's actually being exposed to the cell types that are driving the ARIA phenotype.

And one of the criticisms with the trontinemab data was also with respect to ADA, which you kind of mentioned also with your antibody -- or with your system and even the immuno-inflammatory aspect of trontinemab. So what are the ways you are thinking to kind of derisk your platform concerning these 2 kind of side effects?

That is a really excellent question. So obviously, we try to map out in silico that our shuttles themselves are highly human and highly non-immunogenic. In terms of mapping that into the clinic, I think that's something you really have to keep an eye on. Like when I mentioned ADA of a human antibody dosed into a nonhuman primate, that's not necessarily something you could expect to mimic when you're dosing a human antibody into a human in the clinic. So I think that's just something we're really going to have to keep an eye on in our Phase I safety studies.

And I have my last question, which is for targets related to TREM2 or, let's say, in future, some other immunomodulatory targets, what are the safety implications concerning how much of expression you want to see, especially with respect to these kind of transferrin receptors? And so what are the -- like what kind of safeguards you will have as you are designing these platforms, specifically for immunomodulatory molecules like TREM2?

Yes. I think Dr. An gave a pretty good answer in terms of everything comes down to therapeutic window, right? So how much drug do we need to activate that receptor to the degree that we need to. And then at that dose level, are we seeing unacceptable safety risk. So again, I think it's a really case-by-case phenomenon where we have to evaluate both TfR and potentially CD98-ABC technology particularly because immunomodulatory antibodies might require things like active effector function Fc, which are less compatible, potentially, with the TfR technology. So this is why we think it's great that we have functional shuttles against both.

Our next question comes from the line of Graig Suvannavejh from Mizuho.

This is Charles on for Graig. Just taking a look at the competitive landscape, how does ABC differ from some of the other programs out there, like Denali's and Voyager's? And where do you feel like there is a competitive advantage to be at?

I'll take that one, too. So I think we've worked hard for the last several years to ensure that we're seeing, at the very least, equivalent, but in most cases, better brain uptake than has been at least published for our competitor shuttles. But to be honest, we feel like the really our main advantage in the competitive landscape is pairing best-in-class ABC technology with our portfolio of novel immunomodulatory and neuroimmunology target. So at least to me, I think -- I don't want to say like our technology necessarily blows everyone else's out of the water, but it's really the pairing of best-in-class ABC technology with our portfolio that enables our value proposition.

Our next question will come from line of Corinne Jenkins from Goldman Sachs.

This is Omari on for Corinne. A question for us is how should we take about the level of GCase enzyme needed to restore normal levels of glycosphingolipids?

Yes. Maxime, do you want to maybe comment there?

Yes. Thanks for this question. So in GBA mutation care, Parkinson's disease patients, the reduction in GCase activity is about 30% to 50% compared to non-GBA mutation carriers. So this is what we're targeting to fully restore as far as GCase activity. And the data that we shared with you today is sort of on that scale of activity that we're achieving in vivo in mouse.

Maybe a follow-up question is, do you think you need to restore above-normal or level above normal for -- to see clinical benefit?

So I think that will come mostly for -- from pharmacodynamic readout, as mentioned earlier. So we'll be measuring -- what we want to achieve is a reduction or normalization of the substrate levels. And that is what we're going to determine in vivo by testing different amounts of GCase-ABC and see what is the minimum amount required to restore normal glycosphingolipid levels in the brain of genetically engineered murine models. So that's data to be determined yet, to be shared at a later time point.

Well, we appreciate all the detailed questions, including some that came in on the chat that we didn't have time for, and we'll look to follow up on those. And we want to thank everyone for their time today. With that, I think we'll turn it back over to the operator to conclude the call.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect. Everyone, have a great day.