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

Yes. Okay. Good day, and thank you for standing by. Welcome to the Alector Pipeline Webinar, Advancing Next Generation Medicines for Neurodegeneration. At this time, all participants are in a listening mode. After the speakers' presentation, there will be a question and answer session. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Arnon Rosenthal, Chief Executive Officer. Please go ahead.

Good morning and welcome, everyone. As you heard, I'm Arnon, Alector CEO and Co-Founder. We don't see each other, but there are over 150 people registered for this seminar. So, I'm looking forward to a lively Q&A session after the presentation. So, for the people who know Alector for the last 10 years, you should know that we are now a very different company than we were in the past. Our mission remained the same, our resilience remained the same, but our strategy has fundamentally changed. In the last 10 years, we have developed immune checkpoint therapies for the brain immune cells as a therapeutic strategy for neurodegeneration. We now have an emerging portfolio of bispecific antibodies, enzymes, and nucleic acid therapies that are all driven by our blood-brain barrier technology and address more validated targets. So, the probability of technical success of our second-generation targets is significantly higher than the completely novel targets we have pursued in the past. Evidence for our change in trajectory and reinvention, the first evidence is the recent licensing agreement that we have just done with the Genentech Roche organization. This was on a brain-enabled lysozyme enzyme called GCase that was dedicated as a therapy for Parkinson's disease and ultimately Lewy body dementia. This was an engineering tour de force where we optimized the blood-brain barrier technology, our Alector brain carrier, with regard to affinity, configuration, binding kinetics, and in parallel, we spent several years engineering the enzyme itself, which is naturally a very unstable molecule, to make it up to 50 times more stable and more potent. The combination of our engineered blood-brain barrier technology and the enzyme led to a unique drug that can be delivered peripherally, enter the brains, enter lysosomes, and can replenish a missing GCase enzyme. To the best of our knowledge, we were the only one in the world who were able to achieve this feat, and the Roche Genentech organization recognized that. And despite the fact that they are the premier company for blood-brain barrier technology, and they have significant focus on Parkinson's disease, they decided to partner with us. And this partnering really provides us both with validation of the technology and a significant runway extension that enables us to take multiple drugs to the clinic. The second evidence that we are reinventing our Alector and new companies are increasing new pipeline. We now have, as I mentioned, bispecific antibodies, and today we will discuss our brain-enabled anti-A beta antibodies, as well as an increasing in size portfolio of brain-enabled siRNA. Today we will discuss our brain-enabled tau siRNA and our brain-enabled alpha-synuclein siRNA. Starting with our brain-enabled brain carrier, AL137. You all know about Alzheimer's disease, but just to remind you, Cowen recently wrote a report about Alzheimer's disease, where they assess the future market of next generation Alzheimer's drug to be $70 billion, so it's a pretty meaningful market. There are expected to be over 90 million Alzheimer's patients by 2050. And although Alzheimer's is considered a cognitive disorder, it's quite a bit more. More than 2 million people die of Alzheimer's disease every year. And today, despite several approved drugs, there are really no meaningful disease modifying therapies for this disorder. As you know, the most significant treatment cause of Alzheimer's disease, or one of the two main causes, is the pathological beta-amyloid peptide. This is a 42-amino acid peptide. And this is the main target of Alzheimer's disease therapy now. And there are two approved anti-A beta antibody drugs and multiple additional antibodies against the beta amyloid in the pipeline. We have developed a drug which we think contains the best-in-class features to make it a very competitive drug in this crowded field. So as you see on the left side, our drug recognizes a toxic version of the beta amyloid. This is the pyroglutamate 3 version of the A beta peptide. This is a clinically validated epitope that was shown to be effective by Remternetug, which is an approved drug made by Lilly, and by Donanemab, which is a Phase 3 drug also by Lilly. So this is a clinically validated epitope. We also have what is called the full effector function. When I talk about effector functions, I mean amino acids, amino acid sequences that are designed to recruit immune cells. As I'll discuss further, these amino acids and recruitment of immune cells are really critical in order to remove A-beta plaques. In addition, we have a unique Alector brain carrier, which recognizes the transferrin receptor as a Trojan horse; it leads to a very potent brain entry of the drug. And also because of the unique epitope that we are employing, it has significantly reduced anemia risk, which is a main side effect of the transferrin-based brain shuttles. I will go over each of these features in more details in subsequent slides, but before I do that, I want to really articulate our understanding of how beta amyloid antibodies work in the brain. If you look at the bottom three panels, what happens is that when you inject an anti-AB antibody into the bloodstream, it enters the brain. It has to recognize a toxic version of the beta amyloid plaque. It decorates it, and then it uses again, the effector function, the amino acid sequence on the constant region of the antibody, to recruit the immune cells of the brain, the microglia, and the microglia then decorate the plaque, and start digesting it, phagocytosing it, and removing it from the brain. So an antibody has to have three features in order to be clinically effective. It has to be able to enter the brain at sufficient concentration. It has to recognize toxic versions of the beta amyloid plaques. And it has to be able to recruit the immune cells in the brains to clear the A-beta plaques. These are just the surveyors. They just tag the regions where the plaque resides, but the actual excavators, the actual entities that remove the plaques are the microglia, the immune cells. If you can't recruit immune cells, as you see in the top three panels, you can enter the brain, you can tag the A beta plaque, but if you don't recruit the excavators, you don't remove the plaques and you don't impact the disease. Again, this will become very important in subsequent slides where I discuss the importance of the ability to recruit immune cells to plaques. So going back to AL-137, we systematically checked every feature of the drug to make sure that it has the potential to be first in class. Here you see staining of A-beta plaques on human AD brain sections by AL-137 on the top. You see extensive recognition of A-beta plaques. We consistently compare to the validated drug, Remternetug, and you see on the bottom, very similar staining by Remternetug. So again, this validates our argument that we have a valid clinically validated epitope on the drug. Our antibody not only recognizes a beta plaque, it is also able to recruit immune cells to phagocytose, to digest a beta plaque. On the left side, you see complex culture of human microglia, neurons, and astrocytes that were seeded with beta amyloid. You see if you just have beta amyloids and microglia on the top left, you see some digestion of beta amyloid as reflected by the red dots, but if you add our antibody on the bottom right, under the subheading AL137, you see many more red dots, suggesting that a lot more A-beta peptide entered microglia with the assistance of the antibody and got digested. The more red dots you see, the more A-beta digestion is happening. This can be quantified on the right side, you see a time-dependent digestion of A-beta plaques or A-beta. In blue you see our antibody, 137, and in purple you see the two validated antibodies, Remternetug and Donanemab, that show very similar time-dependent phagocytosis. Again, supporting the notion that we are targeting a clinically validated epitope. Going back now to the effector function, as I said, antibodies need to be able to recruit immune cells to remove beta amyloid plaques. And this requirement was demonstrated clinically repeatedly over the last 10 or so years, 15 years. Today, all the antibodies that show ability to extensively remove A beta plaques and to show clinical benefits are antibodies that have full effector functions. The most potent effector function possible is present in the antibody subset IgG1. IgG1 is able to actively recruit the immune cells in the brain to multiple what's so-called Fc-gamma receptors and instruct them to remove A beta plaques. So the antibodies like Lecanemab, Donanemab, which are now on the market, Aducanumab, which was approved but was removed from the market, and two Phase 3 antibodies, Lecanemab and Donanemab, all have full IgG1, unmodified, unchanged IgG1, and they all show extensive plaque removal exceeding 70%. And this is more or less the threshold that you need in order to start eliciting clinical benefit. In context, on the right side, you see five different antibodies that have reduced effect of functions. IgG4, IgG2 have weakened ability to recruit immune cells compared to IgG1. All these antibodies failed clinical trials. The most recent one is Acumen's drug, which has again an IgG2, a reduced effector function. They were able to show reduction of 25% in plaque level with very high dose of an antibody of 60 mg per kg. We know very well from another antibody, Gantenerumab from Roche, that 25% is not sufficient to elicit any clinical benefit. Gantenerumab reduced A-beta plaques by 60%, and this was not enough to elicit clinical benefit. So today, again, no anti-A-beta antibody with any type of modified effector function has shown to be able to extensively reduce ABT plaque or to show clinical efficacy. So the first generation reduction in effector function was designated to reduce the ARIA side effect, but basically it led to lack of clinical benefit. Despite that, there are multiple antibodies with blood-brain barrier technology that are still being developed with modified effector function. This time the reason for the modification is to reduce anemia risk, which, as I mentioned, is an on-target safety risk of using the transferrin receptor as a Trojan horse. So I just list here four antibodies from AbbVie, from Denali, from Corsana, and from Acumen that are using reduced effector function in different clinical stages. And again, because of our clinical history, in our view, any modification of effector function is not clinically validated and constitutes efficacy risk. There is only a subset of anti-Abeta antibodies with brain-enabled that still have full effector function. The most prominent is Remternetug, which we think is going to be an amazing drug. And as I mentioned, our antibody also has a full effector function. And we think the fact that we have a clinically validated effector function, a clinically validated epitope, it suggests that our drug is significantly less risk of efficacy. As I mentioned, in addition to recognizing toxic A-beta plaques and ability to recruit immune cells, you have to enter the brain at sufficient concentrations. And our Alector brain carrier technology is very potent in facilitating that. Here you see on the left top and on the right top, 30-fold increase in the level of our drug following peripheral injection with the blood-brain barrier technology. Fold elevation is a relative measure because it depends on how well your naked antibody enters the brain. So we also try to calculate absolute concentration in the brain and compare it to published competitors. And although this is again, a cross-study comparison and a lot of extrapolation, our analysis suggests that L137 with our Alector brain carrier is significantly more potent in facilitating brain entry than any competitor that has been published. So again, we have a drug that recognizes the clinically validated epitope, the pyroglutamate, has a full effector function that was clinically validated by four different antibodies, and has exceptional ability to enter the brain, again, surpassing competitors as far as we can tell. Since measuring drug level in brain extract does not really tell you that the drug goes into the right place, we also looked at drug penetrance in intact brain sections. This is an Alzheimer's mouse model. You see on the two left sides antibodies, either an isotype control or our anti-Abeta antibody without brain carrier, our brain carrier technology. The antibody is concentrated around the choroid plexus, which has leaky blood vessels with high blood flow. There is much less drug throughout the brain and there is clearly not homogeneous distribution. In contrast, with our Alector brain carrier following peripheral injection, you see very clearly that the antibody entered the brain, recognized A-beta plaques and bound to them. So basically, every A-beta plaque that is present in the brain can be decorated by an antibody. As I mentioned, the next step, if you have a full effector function, would be to recruit the immune cells to remove these toxic A-beta plaques. Because of the potency of our drug and our brain-enabled technology, we think that with a single-digit low-dose antibody with subcutaneous administration, we can get sufficient exposure in the brain. This is illustrated here. Again, comparing to published and predicted data from Remternetug, we chose extremely strong efficacy. Remternetug is being delivered by IV. Because it's delivered IV, as you see in the blue graph on the left, you have a very high bolus of concentrations in the periphery. This high concentration is associated with the anemia risk, with the infusion reaction risk, and possibly also with ARIA risk. We, in contrast, deliver the drug subcutaneously. You see in the orange graph a much more modest elevation in the periphery, which among many other things will mitigate infusion reaction risk, anemia risk, and ARIA risk. In contrast to the periphery, if you look in the brain, Remternetug still has decent exposure, and this exposure is more than sufficient to elicit very rapid plaque removal. But we, with subcutaneous delivery at half the dose, get very sort of at least two-fold higher exposure in the brain. So again, subcutaneous delivery with our drugs compared to IV delivery with Remternetug. Remternetug is delivered at 3.6 mg per kg in Phase 3. We have delivered our drug, and this is a predictive model, but we predict that our drug at half the concentration will have double the exposure. So because of the potency of our technology, we think that we can have very significant and superior exposure in the brain. Looking at safety, which is a major required feature for anti-Abeta antibody. Again, our focus is on subcutaneous delivery. We think it's more convenient, it's safer, it's scalable. The ultimate goal is to do at-home, monthly subcutaneous delivery. So because of the potency and the features of our drug, we don't even bother with intravenous delivery. We go only to subcutaneous. We did IND enabling studies. We did see transient reduction in reticulocytes, which recovered very quickly and did not lead to any hematologic adverse effects, and we didn't detect any other adverse finding. And no adverse effect dose that we tested is very sufficient to continue with our clinical development, which I'll describe in the next few slides. We are able to develop a very potent brain delivery, which requires somewhat higher affinity binding to the transferrin receptor and still has a full effect of function, which we think is a critical requirement for clinical benefit because we have a unique epitope on the transferrin receptor. So on the left side, you see crystal structure of the transferrin receptor in dark and light blue and the transferrin ligands in yellow and green. Since you don't want to disrupt iron transport to the brain or to reticulocytes, you don't want to bind your Trojan horse in regions that disrupt transferrin binding. Everyone is binding their drug, their transferrin binding epitope, into this dark blue and maybe in the region of the light blue. Most of the companies in sort of the first generation antibody transferrin technology are binding in this region. This includes Corsana, Denali, and Roche. This is a very immunogenic epitope, easy to generate binding antibodies. But because it's so exposed, it's easy for the antibody to also bind immune cells. So the antibody will bind reticulocytes to the transferrin receptor and at the same time can bind immune cells to the effector function that recruits natural killer cells and macrophages. This co-binding of reticulocytes and innate immune cells leads to damage of reticulocytes, and this is what causes the anemia. Our epitope is more secluded, is more masked, and if the antibody binds our epitope, its ability to co-bind immune cells to the Fc-gamma receptor is significantly curtailed. And as a result, the anemia risk is significantly reduced. In contrast, when our antibody binds A beta there is no impediment to recruit immune cells. So our antibody is fully effective in recruiting immune cells in the context of A beta plaques, but it has significantly reduced ability to recruit immune cells to reticulocytes. And this is just briefly illustrated on the four white panels, you see that an antibody that binds the exposed epitope, even if it has a crippled effector function, this Lala PS that's being used by Denali to mitigate anemia risk, even with this mutation, at least in our configuration, you see that this antibody and hemolytic anemia is measured by reduction in red blood cells and in hemoglobin. In contrast, when you have an antibody even with a full effector function that we are using, binding to our unique epitope at the same affinity as the antibody that's using the exposed epitope, we don't see any evidence of anemia in this parallel experiment. So again, we have a drug that binds a clinically validated epitope on A-beta plaques, can fully recruit effector functions validated by four antibodies, and has a unique mechanism transferrin binding domain that facilitates very potent brain penetration with significantly reduced anemia risk. As you know, this is a very crowded field, meaning there are at least 16 antibodies with different brain enablement technologies that are being advanced in the clinic. But despite the crowded field, at least in our view, we think that only a small subset of them have the three required features: ability to enter the brain safely, ability to bind plaques, and ability to recruit immune cells effectively. So we think that only a subset of these antibodies will actually end up being effective in the clinic. So just briefly to look, talk about some of these. AbbVie and Aliada have a completely inactivated effector function. They are not going to be able to recruit immune cells through the Fc-gamma receptor. We think that there is a significant efficacy risk. Likewise, Corsana and Denali have modulated the effector function that in our view also represents efficacy risk. Novartis and Oryzon, again, there are no formal publications, but we think that they are using CD98, which is an unvalidated blood-brain barrier technology, which has possible efficacy risk. Acumen also is using reduced effector function, which in our view constitutes efficacy risk. And others, exposed using either exposed epitope like Remternetug with Roche that would lead to some anemia risk and infusion reaction risk. So we think that despite the crowdedness of the field, AL-137 will stand out because it has a validated epitope, full ability to recruit immune cells, superior brain exposure that surpasses the competitors, and very favorable safety profile and ability to be delivered subcutaneously. We are planning to go to the clinic no later than April of next year. We are going to do Phase 1 initially in healthy volunteers, but the second section of the Phase 1 will be in patients, and in both healthy volunteers and in the patients, we are going to assess safety, including hematologic safety, infusion reaction safety. We are going to look at exposure, as I'll show you in the next few slides. Although you cannot measure exposure in the brain properly, you can measure exposure in the CSF, and in our hands, based on non-human primate studies, exposure in the CSF is very predictive of exposure in the brain proper, and this will allow us to really validate the efficacious dose in human. And we are sort of targeting very aggressive goals, basically removal of around 90% of amyloid plaques with monthly dosing within three to six months. The removal of the beta plaque should be also supported by multiple serum and CSF biomarkers. We are looking for good safety again, low anemia, very manageable anemia rate, a low injection reaction, that's a major liability for Remternetug and required steroid pretreatment and low ARIA. This is just a schematic summary of our Phase 1 in healthy volunteers that's going to be conducted in Australia, targeting starting in April, going to be four different doses, basically covering multiple folds around what we predict to be the efficacious dose. And again, there are going to be multiple safety and exposure measurements. And I repeat myself, but I want to really emphasize that because we have a validated epitope, validated effector function, if this safety study that's going to conclude by the end of Q2, early Q3 '27, if this safety study is going to conclude by the end of Q2, it looks favorable, we think that the overall risk of 137 will be significantly reduced because the efficacy component has been validated many times by other antibodies. I said that the serum or CSF exposure is predictive of brain exposure with our drug and this is just demonstrating that. This is peripheral injection of our drug at 3 mg per kg in non-human primates, you see significant elevation in the CSF and corresponded elevation in the brain tissue proper. So knowing the concentration in the CSF, in this case it was close to 200 nanogram per ml, will really tell us with high certainty what's the expected exposure in the brain proper and will tell us whether we reach an efficacious dose. This is a summary of the Phase 1b in patients. This will be conducted both in the U.S. and Australia. It's going to be multiple monthly doses. Again, we are doing two doses encompassing what we consider to be the optimal efficacious dose. We are going to conduct multiple PET imaging for A-beta plaques. We are going to conduct multiple serum and CSF biomarkers, including p-tau217, which is a strong indicator of A-beta plaque reduction. We are going to measure all the safety parameters again, hematologic risk, injection, infusion-related reaction, ARIA risk. So by Q3, Q4 of '28, we will have a very extensive package of safety and biomarker and imaging-based efficacy readout with our drug that will really tell us if we have a competitive safe drug that can be delivered subcutaneously. This is just summarizing this program. As I mentioned, we are doing Phase 1 in healthy volunteers in Australia. First in human is targeting around April next year. We are going to file an IND in parallel soon after that will enable us to go back to the U.S. for patients. By Q3 '27, we will have an extensive safety and exposure package. And starting Q4 '27 all the way to Q4 '28, we will have accumulation of efficacy data that includes PET imaging, biomarkers, multiple safety measurements. And as I hope I was able to convince you, AL-137 has the potential to be best in class. It has a de-risked Abeta epitope, has a de-risked effector function that was validated with multiple antibodies, has exceptional brain exposure, and has very favorable safety, including hematologic safety. It is going to be delivered subcutaneously and because of the low dose, we don't think that we will need any special technology to deliver it subcutaneously. We have a very productive manufacturing process that will lead to very low cost of goods. That's also a requirement to be competitive in this field. We now go into our siRNA program that Eric Brown will present. This is a very exciting feature of Alector. This is an expanding platform that's going to be plug and play. We have identified what we consider to be best-in-class shuttle for siRNA, and we can apply the same shuttle for multiple cargos. So we view this as one of the more exciting programs at Alector that will expand very significantly. So Eric, to you now.

Hello, I'm Eric Brown. I've been leading up the work on our ABC program for the last seven plus years at Alector. So our goal for our siRNA therapeutic platform has been to enable safe, convenient, and infrequent dosing with both best-in-class brain uptake and target knockdown. And you can see a few factors that go into this on the next slide. So one of these, as Arnon mentioned, is optimizing the shuttle. So the need for a shuttle to deliver an siRNA is slightly different than for an antibody because you need to deliver into the brain and into target cells within the brain. But we feel like we've sort of optimized both the binding affinity and kinetics to maximize this uptake. We've also focused from the start on subcutaneous delivery and importantly on making sure we have a safe and tolerable platform. So we've actually dosed up to 30 mg per kg siRNA equivalent dose, which is equivalent to 250 mg per kg for the total molecule, and not seen any adverse effects on hematology, including changes in reticulocytes. Because of some of these features, we've been able to demonstrate strong brain uptake of multiple siRNA cargos in the non-human primates of up to over 100 nanomolar after subcutaneous administration. And critically, the brain uptake that we see with our platform is far more homogenous across different brain regions than what has been seen with IT dosing of non-BBB enabled oligotherapeutics. So, on the next slide, we have on the left side combined data from multiple internal NHP studies that have demonstrated that the ABC chosen for our siRNA platform is ideally balanced for siRNA uptake. We've actually taken molecules with the same epitope, and this is the same optimized ABC epitope used for the A-beta program. And we've tested ones with either stronger or weaker affinity to TFR. And in each case, they have lower brain accumulated siRNA uptake than what was seen with the lead brain carrier. And another proof on this side is on the right side of this slide, where we actually in-house made published competitor anti-MAPT antibody oligoconjugates from both Arrowhead and Lilly, and did a subcutaneous dosing regimen into mice and looked at the level of antisense siRNA that was present at the end of the study. And actually we see best-in-class brain uptake for our platform and consistently lower uptake for both the Arrowhead and Lilly platform. So we think this is pretty good proof that we have at least competitive, and I think we would say best in class, uptake of siRNAs into the brain. Then our first antibody oligo conjugate program I'll talk about is AL164. This is an ABC-enabled MAPT-targeting siRNA for treatment of Alzheimer's disease and primary tauopathies. So as a lot of you probably know, tau aggregation is a hallmark of both Alzheimer's disease and primary tauopathies, such as progressive supranuclear palsy or PSP. So the evidence that tau drives neurodegeneration is very strong. Genetically, mutations in the tau gene alone are enough to cause familial tauopathy. And in Alzheimer's, tau burden, not amyloid, has been shown to be predictive of where and how fast the brain degenerates. PSP is rare, but it progresses even faster, with median survival of only about six years after symptom onset. An important factor in tau pathology is that it builds up inside of neurons, which puts it largely out of reach of antibody therapeutics. Two different anti-tau antibodies nearly eliminated free tau in the cerebrospinal fluid of PSP patients, yet neither showed any clinical slowing of the disease. This is why we're pursuing a different strategy by lowering tau production at its source, inside of neurons throughout the brain. So, if we look forward to the design criteria for AL164, as I mentioned in the last slide, antibody therapy for tau has largely been ineffective, likely due to the intracellular nature of the pathology. The next generation of tau-targeting therapies include unconjugated oligos such as Biogen's [diranersen], which have started to show a lot of improvement in the show signs of clinical benefit and we think provide good proof of concept for the tau lowering approach. In their Phase 2 CELIA study, they were able to show reduction in CSF total tau by 50% to 65% and lowered tau-PET across all doses. So this led to a slowing of clinical decline on five of the six pre-described endpoints, although it did not meet the primary endpoint of dose-dependent response on CDR-Sum Box. So what we think this molecule didn't solve is delivery. [Diranersen] is an unconjugated oligo given by intrathecal injection, and the intrathecally delivered oligos show a steep exposure gradient with poor drug accumulation in deep brain regions. Our solution to this problem is AL164, which combines a potent anti-tau siRNA with the Alector brain carrier that's been optimized for best-in-class brain uptake and homogeneous brain biodistribution after subcutaneous injection. Another important factor, unlike the A-beta example, is that these antibody oligo-conjugate molecules do not rely on antibody effector function. This is the opposite of what Arnon has been mentioning the rest of the talk. In this case, unlike with an A-beta antibody, we can ablate binding Fc receptors and eliminate any residual hematologic tox risk without having any effect on the potency of the siRNA. The next slide demonstrates the superiority of peripheral injection combined with ABC technology over intrathecal delivery. So, following subcutaneous administration of AL164, it enters the bloodstream and is translocated into the brain through receptor-mediated transport at capillaries, which allows for homogenous biodistribution. IT-dosed oligos, such as [diranersen], in contrast, are dosed into the lumbar spinal cord and rely on passive diffusion through the CSF to reach the brain, leading to a highly heterogeneous distribution. We designed AL164 to go into the clinic with a subcutaneous route of administration from the start, potentially allowing for home administration, which is going to be necessary to address the enormous global patient population. This also removes the need for any sort of specialized facility for dosing, as well as the safety complications inherent in intrathecal dosing. We believe that at least part of the limited clinical benefit seen with [Diranersen] was due to the limitations of IT dosing and that the peripheral route of administration will offer significant advantages in the clinic. Moving on, the siRNA component of AL164 was designed to have high potency across all isoforms of tau, as well as strong cyno cross reactivity. Some of the data shown here and on subsequent slides was made using the parental AL064 siRNA, which you may have seen in previous iterations of this talk. The siRNA used in our lead compound AL164 has the same sequence as AL064, but includes additional chemical modifications to enhance the stability of the siRNA, and thus the duration of knockdown without impacting its potency. So with this siRNA, we were able to demonstrate in vitro potency of approximately 21 picomolar IC50 for MAPT knockdown in the MCF7 cell line via transfection of the naked siRNA. We were also additionally able to confirm knockdown of MAPT by the full conjugate molecule in an iPSC-derived neuronal system. And this system takes advantage of the natural TFR-mediated uptake. So this is not artificially transfecting, and this is the real effect that you would expect to see in vivo. So moving forward, going into mice, we were able to see up to 81% knockdown of MAPT mRNA in relevant brain regions following a three subcutaneous loading dose approach. And just to explain a little bit, this three loading dose approach is very commonly used in the field for siRNA delivery and is then designed to be followed by single doses to maintain durability of the response. And to show that durability, on the right side of the slide you can see a single subcutaneous dose of AL164 was actually shown to be able to maintain up to or greater than 50% tau knockdown at over two months. So this really informs what our sort of final clinical strategy will be if we move forward. So these next three slides show data from a proof of concept non-human primate study conducted with the parental AL064 antibody oligo conjugate. The left side of this slide highlights the homogeneous brain biodistribution of peripheral dosing with ABC technology. So if you look at the gray bars, you can see that they're consistently high across all brain regions tested with a maximum variability of maybe threefold. I have to say this putamen data is worse than we've seen in other, it's usually within like 1.5 to 2-fold across brain regions. In contrast, if you look at the blue bars, we have an intrathecally dosed unconjugated version of the AL064 siRNA. In this case, you do see high uptake into the spinal cord region, which makes sense because that's where it's intrathecally dosed, but you see much lower and much more varied variable uptake into the actual brain regions that we want to target. Then on the right side of the slide, you can see cellular level uptake of AL064 in the non-human primate cortex via an RNA scope assay. In this data, you can see in red, the AL064 siRNA and in green a neuronal marker. And then if you look on the far right side, the yellow color is co-localization of the two markers showing that we're really delivering siRNA into the critical cortical neurons that we want to protect during Alzheimer's disease. If we move forward to the actual level of knockdown we were able to see, we see up to 60% to 70% knockdown of Tau mRNA across critical brain regions, such as the hippocampus and cortex, two weeks post the final dose. Then one quick note for this study, this study was a proof of concept study that was conducted with IV infusion, but subsequent studies were conducted with subcutaneous administration as that is the planned final route of administration. If we go forward to look at durability, which is ultimately one of the most important factors for an siRNA drug, we were able to show that the peripheral dosing of AL064 led to a sustained decrease in phosphorylated tau217 levels in the non-human primate brain at both day 28 and day 98. So day 98 is actually three days post the final dose and we're still seeing the sustained decrease, as well as a sustained drop of approximately 45% in the CSF at 70 days post-dosing. So the sustained knockdown of phospho-tau217, even with the parental less stable AL064 siRNA, is giving us a lot of confidence that we can achieve a one-month or greater maintenance dosing regimen in the clinic with AL164. And then obviously we wanted to confirm that the brain uptake is at least as strong and the knockdown is at least as strong with the actual AL164 molecule. So this is the lead candidate dosed subcutaneously into non-human primates with the same three times subcutaneous loading dose approach. And we're seeing now up to 76% mRNA knockdown in the non-human primate brain. And as you can see, it's quite consistent across brain regions. One thing to note here, the durability arms for this study are still ongoing, but obviously we expect durability to be at least as good or better than what was seen with AL064, given that the only change between the two molecules is additional siRNA chemical modifications to enhance in vivo stability. And then really critically coming out of both of these studies, we didn't see any AL164 or AL064-related adverse events following IV or subcutaneous administration at doses of up to 30 mg per kg siRNA equivalent, which as I mentioned before, is roughly 250 mg per gig total drug dose. And this includes no TA-related changes in both reticulocytes or other hematological parameters. So we're currently initiating CMC work for AL164 with a planned first in human date of Q2 2028, with subcutaneous delivery being the planned route of administration from the start. To support this route of administration, AL164 has been shown to be able to be concentrated up to 150 mg per ml and still be well within the acceptable viscosity limit for subcutaneous administration. So we're pretty excited about moving this drug forward. And as Arnon mentioned, part of the plug-and-play nature that enables the CMC is that we're using actually the same ABC shuttle for this program that we'll be using for the next program that I'll talk about, AL062. AL-062 combines a highly potent and selective anti-synuclein siRNA with the same validated Alector brain carrier utilized for 164. So if we look at synuclein, as probably many of you know, alpha-synuclein is the defining pathological protein in Parkinson's disease. So it misfolds and accumulates into what are called Lewy bodies, which are intracellular inclusions and are a hallmark of both Parkinson's disease and Lewy body dementia. Alpha-synuclein is genetically linked to both the development and progression of Parkinson's disease. Duplications and triplications of the synuclein gene cause familial Parkinson's, and more copies have been shown to lead to both earlier onset and more severe disease. So the affected patient population for these various synucleinopathies is both large and growing. Nearly 12 million people worldwide were living with Parkinson's in 2021, and that's been projected to more than double by 2025. In the U.S. alone, Lewy body dementia accounts for an additional 1.4 million patients. And similar to the tau example, antibodies have not been shown to be able to deliver for synuclein. [Biogen synpanamab] was fully negative in Phase 2, and Roche's Prasinezumab has missed its primary endpoint twice in the PASADENA and PADOVA studies. At this point in time, there's still no approved therapy that slows progression in either Parkinson's disease or Lewy body dementia, leading to a very high unmet medical need. So as I mentioned, similar to tau, the reason synuclein is difficult to target with antibody therapeutics is due to the largely intracellular nature of the pathology. Again, redesigned an antibody oligo-conjugate molecule that delivers a highly potent anti-synuclein siRNA directly into neuronal cells within the brain. And as I mentioned before, because the key design criteria for the ABC portion of this molecule, essentially driving the highest possible brain uptake of the siRNA, is the same between AL164 and AL062, we're actually using the exact same demonstrated highly safe and manufacturable ABC for both programs. If we move on to the siRNA used in AL162, we've showed it to be extremely highly potent with a 3 picomolar IC50 and 84% maximum knockdown in vitro, and importantly also highly specific with no significant off targets noted even at very high levels. High transfected siRNA concentrations. So if you look at the off-target data on the right side of this slide, we've actually transfected the parental AL062 siRNA up to 50 nanomolar concentration in both HEP3B and SHSY cells. And we didn't see a single off-target gene reduced by 50% or more. And if you compare this to on-target potency, that's actually four orders of magnitude higher than what's required for the on-target knockdown of more than 50%. So this is highlighting how highly specific this siRNA is, which is important for the safety margin in vivo. Moving into mice, we were able to dose human transferrin receptor knock-in mice with AL062 using a 3x3 mg per gig subcutaneous loading dose approach. And just to note, the synuclein siRNA we're using here is fully human, non-human primate, and murine cross-reactive, so we're able to do these studies directly in human transferrin receptor knock-in mice. So at day 29, we're able to see a high and consistent AL062 siRNA accumulation. Similar to 164, we're seeing approximately 100 nanomoles across multiple brain regions. And this level of brain uptake was associated with a consistent knockdown of the murine-synuclein gene of approximately 90% across multiple brain regions. So obviously this was pretty exciting to see when we moved into non-human primates with the same three times subcutaneous loading dose approach. And we're actually able to see a very similar level of knockdown in the non-human primates as we were able to see in the murine system. Again, approximately 90% across multiple brain regions tested. So this level of knockdown compares quite favorably to competitor molecules and we think supports rapid clinical development of AL062. And then importantly, similar to AL164, we have not seen any AL062-related adverse events following subcutaneous administration, including, again, no TA-related changes in reticulocytes or other hematological parameters. And we are currently initiating CMC work for AL062 on a similar timeline to AL164. Actually, we're making them at the same manufacturer. And again, because the ABC portion is the same between the two molecules, there's very significant synergy there in the CMC process, and we're actually planning for them to move relatively in parallel and going into first in human in Q2 2028, similar to AL164, also with subcutaneous delivery planned from the start. Thank you for your attention. I'm going to hand it back over to Arnon to wrap things up.

Hello, so hopefully we're convinced that Alector is a new company now with new programs, new technology, and sort of multiple drugs that are going to the clinic. Meaning, as you heard, we've evolved from conventional antibodies to Alector brain carrier-enabled technologies using bispecific antibodies, enzymes, and nucleic acid therapeutics. We recently concluded another partnership with the Genentech Roche organization that extends our runway into 2029 and validates the uniqueness of our Alector brain carrier. We are developing what we consider to be a very competitive anti-Abeta antibody that's, I think, largely validated with regard to efficacy and promising with regard to safety. And we'll have safety data by the middle of next year and efficacy data by the middle to the end of the following year. So we think that this is a sort of the AL137 is a very competitive program with good potency, potential efficacy and safety that will be delivered subcutaneously. And as you heard from Eric, we have an increasing portfolio of brain-enabled siRNA programs starting with the two most validated targets, Tau and alpha-synuclein, but going beyond that with additional targets that we will discuss in future webinars. And again, I want to highlight that with the Genentech partnership, we have runway into 2029 and we can have, we will have at least targeting at least three programs to go to the clinic with these resources. So we will now open the podium for questions and I will stop sharing the presentation.

To ask a question during the session, you will need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. To submit a web question, select the Questions link in your toolbar. Please stand by while we compile the Q&A roster. And our first question comes from Thomas Shrader with US Bank ETIG. Your line is open.

Good afternoon, good morning, wherever you are. Thanks for the presentation. Your presentations are always full of data, so they're very useful. I was wondering, kind of a nerdy question, your NAVI data are quite interesting. Do you have independent data that the epitope is more masked on red blood cells than it is on the blood-brain barrier, which explains the very clean anemia result? I'm going to have a kind of a follow-up.

Do you want to? I can take it. It means I think that it's the same epitope on reticulocytes and on the blood-brain barrier, basically. Basically, the drug can bind the transferrin receptor both on reticulocytes and on the blood-brain barrier, but it cannot co-bind effector function receptors. It cannot bind Fc-gamma receptors. So it cannot recruit immune cells either to reticulocytes or to the blood-brain barrier, but it can still transduce transcytose through the blood-brain barrier fully effectively as we have shown by the brain concentrations of the antibody. So it is a safety feature both for reticulocytes and for the blood-brain barrier. Again, the occlusion or the inability to co-bind immune cells and reticulocytes or blood-brain barrier endothelial cells, does not take place when the antibody binds Abeta plaques. When it binds Abeta plaques, the binding to the plaque is further away from the effect of function, and this frees the effect of function to recruit immune cells completely.

I can follow up with kind of a philosophy approach or philosophy question. Do you see your approach as kind of anti-A-beta oligomer? Because pyroglutamate is quite rare, maybe 2%. And the toxic oligomers are more like 20mers. So I'm not sure you'd expect them to have any pyroglutamate. So do you see this as a fundamentally plaque-driven hypothesis? Thank you.

Yes, I think the majority of the, as you said, the pyroglutamate is a small, constitutes a small percentage of the plaques and of toxic oligomers, but it's exceptionally toxic, it seeds the plaques, it's not present as a monomeric or and it's not present in the periphery. So yes, I do think it's primarily plaque-targeted approach, but also toxic aggregates, soluble aggregates, also contain pyroglutamate. And it's enough to have just a small number of pyroglutamate versions of the peptide to recruit the antibody, to recruit the microglia. And once the microglia are recruited either to the plaques or to oligomers, they don't distinguish between pyroglutamate or non-pyroglutamate peptides. They digest just everything. So this is, again, just tagging the plaque. Once you tag the plaque, the entire plaque will be destroyed by the microglia. And as demonstrated by Donanemab and more recently Remternetug, this epitope is extremely effective in recruiting microglia to the plaques and removing beta amyloids and to lead at least in the case of the Donanemab so far to clinical benefit, which is comparable, if not better than targeting like general and terminal A-beta. But I think there have been multiple evidence that just targeting soluble versions of A-beta without targeting the plaques is not going to be as effective or effective at all.

Okay, thank you.

Thank you. Our next question comes from Pete Stavropoulos with Cantor Fitzgerald. Your line is open.

Hi, Arnon and team. Thank you for hosting this event. Very informative. So a couple of questions for me. You're planning to initiate the Phase 1b MAD study in Alzheimer's patients in second half of '27. You described the overall design, but I'm not sure if I missed it. You know, how many patients are you planning to enroll per arm? Will you include a placebo? Are you going to target a specific population? And will you wait until all cohorts are complete before disclosing data?

Kayan, would you like to take the number of patients and the placebo question? Sorry, Kayan's not on right now. Okay, I'm sorry. So I'll take it then. So the Phase 1a, basically both the Phase 1a and Phase 1b are placebo controlled. The Phase 1a is going to be six patients and two placebo. And Phase 1b patients, I think it's 15 patients and three or four placebo. So they're both, meaning there are going to be four doses in the healthy volunteers, like different dose escalations that, as I mentioned, cover what we predict to be the efficacious dose and from both directions. And for the Phase 1b, there's going to be three doses like what we consider to be the optimal efficacious dose and two doses from each side of it. We are still deciding whether to report intermittent data or not, meaning we haven't really disclosed whether we are going to do that or not. But we are definitely going to report the safety data at the end of the Phase 1a, which is going to be at the latest in Q3 '27, and we will likely sort of report or possibly report efficacy data, at least in the middle of the Phase 1b before the completion.

Okay, and additional question on 137. One of the slides you show suggested that 137 concentrations are a lot higher than competitive programs in the brain. Nanomolar, I believe was the case. What are the properties of the platform or that specific carrier that allows for this differentiated uptake versus your competitors?

Eric, would you like to take that?

I think it's a combination of both the epitope and the affinity. So somewhat similar with the siRNA model, we've across like nine different non-human primate studies optimized really for the highest possible brain uptake. So we've tested molecules with stronger affinity, weaker affinity, and we feel like we've really hit the range that at least for the epitope that we're using maximizes the possible brain uptake. And while it's a little bit different affinity between antibody cargo and siRNA cargo, we feel like we know where it is now for all classes of molecules. But I think that partially does intersect with the epitope, right? So at another epitope, you might have a slightly different optimized affinity.

Or brain penetration. Yes. So I think the unique epitope, the binding affinity, the binding kinetics together really lead to superior brain penetration.

And if you don't mind, one last question. From my understanding, you know, ASO-based therapeutics, like siRNA, you know, they have a higher probability of success versus small molecule and biologic-based therapeutics and can have a shorter development timeline. You know, how are you thinking about the next wave of potential candidates in terms of modality to deliver to the CNS with ABC? You know, are you going to lean more towards one type of modality versus others? And, you know, are you still going to continue to focus on large indications or are you going to venture into rare disease? Yes.

Yes, we are expanding our siRNA platform, as you said, and Eric said. We have a shuttle that can be used for multiple siRNAs, and we have a really good screening process for siRNA, for potency and for minimal off-target activity. SiRNAs is a significant focus of ours. So this is going to be, I think, the main thrust of the company in the near future. We are still not ignoring antibodies or enzymes. We have capability of delivering these. I think it will depend on the targets. Like siRNA, you can knock down targets with antibodies. You can, in enzyme replacement therapy, you can activate receptors or you can substitute missing protein. So siRNAs are really good if you want to remove something, but if something is missing and you want to replace it, you need either enzyme replacement therapy or agonistic antibodies. So we are, it's really, we are looking first at what is the most exciting target for a given indication. What's the strongest, the genetic and biological evidence for the target. And then we will tailor the optimal modality for the specific target. And yes, at this point, we are doing large diseases. But as Eric said, even for the TTR siRNA, there is PSP, which is a rare disease, which we are going to explore. So we are not shying away from either rare disease or large disease, it's really the biological validation and the level of excitement about the target really determines what we are doing.

Thank you very much for taking my questions.

Thank you. Our next question comes from Graig Suvannavejh with Mizuho. Your line is open.

Good afternoon. Thanks for this webinar. Really informative and helpful. Just wanted to ask a few questions. One around kind of what the bar is that you are looking for with respect to amyloid clearance. I know you had mentioned in your presentation that I think, I think it was for Gantenerumab, which showed a 60% reduction that wasn't sufficient. And I think you provided comments that you were hoping to achieve 90%. I was wondering if you could provide more color on how you came to 90%. Also a second question would be similar as it relates to alpha-synuclein. If there's a threshold of knockdown that you're trying to see that you think would translate it to efficacy. And then maybe my last question just on the AL-137 Phase 1b program or trial, do you have a sense that it might be early days, but do you have a sense of, more specifically, what the inclusion-exclusion criteria would be for your early AD patients? I don't know if you're stratifying by a certain range of MMSE or other characteristics of the ideal patient population you want to enroll in that program.

In that part of the Phase 1b. Thanks. So regarding removal of plaque, the minimal threshold for removal that leads to clinical benefit, like if you look at Lecanemab and Donanemab, was 70%. Remternetug was able to reduce A-beta plaques by over 80% within three months and within six months, it was 90% to over 100%. So we were, want to be competitive with Remternetug. So the 90% is sort of a target based on Remternetug's ability to reduce A-beta plaques within six months to this level and having, I think, I think the vast majority of the patients, what's considered to be A beta plaque free, which is less than 24, there are multiple grading now, but less than 24 centiloids now. So again, we think that over time, where 70% is a clinical necessity. I think if you do less than 70%, you're not going to be clinically efficacious. And it's really an interesting question like whether you remove A-beta beyond, say between 70% and 100%, or even beyond 100%, basically below normal level, whether you'll see better clinical benefit, faster clinical benefit. Because of the features of our antibody, we are aggressive with our targets and we think that we can achieve 90% ACI. Be it a plaque removal within three to six months. Regarding alpha-synuclein, what's the threshold? We don't really know. It's like genetically even modest elevation of alpha-synuclein, like there are non-coding region mutations, like promoter mutations that increase alpha-synuclein by only 10% to 20% and they and this is sufficient to cause Parkinson's disease. So it is possible that even modest reduction in alpha-synuclein will be sufficient, but we are targeting at least 50% reduction. As Eric showed, we can reduce alpha-synuclein completely, basically almost to zero, but we'll test anything between. Between 50% to 90% and basically it will depend on the safety. There is really no clear safety database for how much alpha-synuclein you can knock down and still be safe. So I think at least 50% reduction would be our threshold in humans, and we will go, basically we'll do like dose response, both for safety and ultimate efficacy. But it's a much more difficult question than A beta plaques. For patient selection, we are selecting what's called early Alzheimer's disease. They have to have abnormal level of beta amyloid by PET imaging and they have to have abnormal cognitive decline like at the range that's considered like early Alzheimer's disease, though basically quite similar to what all the other anti-AB antibodies used. So we don't, like we are not going to, unlike Lilly, for example, with their latest clinical trial, we are not going to stratify by tau levels. We are only going to stratify by A beta level and by MMSE.

Okay, thank you. Thank you. Our next question comes from Mike on for Sean Laumann with Morgan Stanley. Your line is open.

Hey, this is Mike on for Sean. Thank you for taking our question and hosting the event. Two from us. First one, for the safety readout for AL137 and 3Q, could you help to set any expectations on what would be a good outcome here? Do you want to see a completely clean profile, or would any sort of transient the end reversible impacts to reticulocyte or hemoglobin signal be acceptable? Thanks. And we have a follow-up.

Yes. As you know, Roche in their initial clinical trials reported somewhere between 10% to 20% level of anemia. Actually, in long-term extension studies, the anemia rates went down significantly to something like 4%. So we do think that transient reversible anemia would be acceptable. But we hope to not have even that. But anemia, again, as Roche demonstrated or said, that anemia is a manageable, unless it's really severe, it's a very manageable adverse effect and again with Remternetug, it seems as if the anemia was transient and reversible and they are continuing to Phase 3. So we don't think that, again, transient and manageable anemia would be a showstopper for AL137. But again, we don't see, in our non-human primates, it's like our subcutaneous delivery at a significantly higher dose than what we consider to be the clinically efficacious dose. We didn't see any adverse effect associated with reduction of red blood cells or hemoglobin. So we hope that our drug will be completely clean, but I think we can live with...