Alector, Inc. Aktie

Good day, and thank you for standing by. Welcome to the Alector Pipeline Webinar, Advancing Next Generation Medicines for Neurodegeneration. [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 to 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 lysosomal 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 50x more stable and more potent. And 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 are 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 as a new company is our 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's expected to be over 90 million Alzheimer's patients by 2050. And although Alzheimer's is considered a cognitive disorder, it's quite lethal, 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 antibody 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 recognized 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 donanemab, which is an approved drug made by Lilly, and by remternetug, which is a Phase III 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. And 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 recognize 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. So, if you look at the bottom three panels, what happens is that when you inject an anti-A-beta 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. The antibodies 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. So, 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 AL137, 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 AL137 on the top. You see extensive recognition of A-beta plaques. We consistently compare to the validated drug to the donanemab and remternetug, and you see on the bottom, very similar staining by remternetug. So again, this is validate our argument that we have a valid clinically validated epitope on the drug. Our antibody not only recognize 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. So, the more red dots you see, the more A-beta digestion is happening. And this can be quantified on the right side, you see a time-dependent digestions 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 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 III antibodies, remternetug and trontinemab, all have full IgG1, unmodified, unchanged IgG1, and they all show extensive plaque removal exceeding 70%. 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 effector functions. IgG4, IgG2 have weakened ability to recruit immune cells compared to IgG1.

All these antibodies failed clinical trials. The most recent one is the 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 A-beta 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 listed four antibodies from AbbVie, from Denali, from Korsana 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-A-beta antibodies with brain-enabled that still have full effector function. The most prominent is trontinemab, 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 AL137 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 recognize 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 a 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. And this is an Alzheimer's mouse model. And you see on the two left sides antibodies, either an isotype control or our anti-A-beta 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. But 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. And this is illustrated here. Again, comparing to published and predicted data from trontinemab, we chose extremely strong efficacy. So, trontinemab is being delivered by IV. And 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. And 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, trontinemab 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 trontinemab. trontinemab is delivered at 3.6 mg per kg in Phase III. 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-A-beta 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 study. 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 the 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 effector function, which we think is a critical requirement for clinical benefit because we are utilizing 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. So, 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 the first generation antibody transferrin technology is binding in this region. This includes Korsana, 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. And 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 bind 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 plaques 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 can elicit anemia as 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 transferrin binding domain that facilitates very potent brain penetration with significantly reduced anemia risk. As you know, this is a very crowded field, means 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, Korsana and Denali have modulated effector function that in our view also represents efficacy risk. Novartis and Ossianix, again, there are no formal publications, but we think that they are using CD98, which is an unvalidated blood-brain barrier technology, which with possible efficacy risk. Acumen also is using reduced effector function, which in our view constitute efficacy risk. And other companies have, again, either exposed -- using either exposed epitope like trontinemab with Roche that would lead to some anemia risk and infusion reaction risk. So we think that despite the crowdedness of the field, AL137 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 with subcutaneously. We are planning to go to the clinic no later than April of next year.

We are going to do Phase I initially in healthy volunteers, but the second section of the Phase I will be in patients, and in both healthy volunteers and 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 over around 90% of amyloid plaques with monthly dosing within 3 to 6 months. The removal of the A-beta plaque should be also supported by multiple serum and CSF biomarkers. And we are looking for good safety again, low anemia, very manageable anemia rate, a low injection reaction, that's a major liability for trontinemab and required steroid pretreatment and low ARIA.

This is just a schematic summary of our Phase I 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 looks favorable, we think that the overall risk of 137 will be significantly reduced because the efficacy component has been validated many times in by other antibodies. I said that the serum and 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 Ib in patients. This will be conducted both in the U.S. and Australia. It's going to be multiple monthly dose. 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. And 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 summarize this program. As I mentioned, we are doing Phase I 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 and multiple safety measurements.

And as I hope I was able to convince you, AL137 has the potential to be best in class. It has a de-risked A-beta 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. And 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. And we have a very productive manufacturing process that will lead to very low cost of goods. That's also is 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. So, 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 7 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. So, 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 6 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. And 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 signs of clinical benefit and we think provide good proof of concept for the tau lowering approach. In their Phase II 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 5 of the 6 pre-described endpoints, although it did not meet the primary endpoint of dose-dependent response on CDR Sum of Boxes. So, what we think this molecule didn't solve is delivery. Diranersen is an unconjugated oligo given by intrathecal injection, and the intrathecally delivered oligo 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 AD-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 2 months. So this really informs what our sort of final clinical strategy will be. If we move forward. So these next 3 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 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 RNAscope 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, 2 weeks post the final dose.

And 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 phospho-tau217 levels in the non-human primate brain at both day 28 and day 98. So day 98 is actually 83 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 1-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 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 kg 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. So, AL062 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's cinpanemab was fully negative in Phase II, 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. So again, we designed 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 three picomolar IC50 and 84% maximum knockdown in vitro, and importantly also highly specific with no significant off targets noted even at very 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 SH-SY5Y 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 3x 3 mg per kg 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 nanomolar 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 3x 3 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 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. Means, 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-A-beta antibody that's, I think, largely validated with regard to efficacy and promising with regarding 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.

[Operator Instructions] Our first question comes from Tom Shrader with U.S. Bank BTIG.

Your presentations are always full of data, so they're very useful. I was wondering, kind of a nerdy question, your anemia 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? And then I have a follow-up.

Do you want to? I can take it. Means, I think that it's the same epitope on reticulocytes and on the blood-brain barrier. 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 anti-A-beta binds A-beta plaques. When it binds A-beta plaques, the binding to the plaque is further away from the effector function, and this frees the effector 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 pyroGlu 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 pyroGlu. So do you see this as a fundamentally plaque-driven hypothesis?

Yes, I think the majority of the, as you said, the pyroglutamate is a small -- constitutes a small percentage of the plaques 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 N-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.

Our next question comes from Pete Stavropoulos with Cantor Fitzgerald.

A couple of questions for me. You're planning to initiate the Phase Ib 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.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?

Caiyan, would you like to take the number of patients and the placebo question?

Sorry, Caiyan's not on right now.

Okay, I'm sorry. So I'll take it then. So the Phase Ia, basically both the Phase Ia and Phase Ib are placebo controlled. The Phase Ia is going to be six patients and two placebo. And Phase Ib patients, I think it's 15 patients and 3 or 4 placebo. So they're both, means 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 Ib, 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, means 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 Ia, 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 Ib 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. 28 nanomolars, 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 9 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 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. How are you thinking about the next wave of potential candidates in terms of modality to deliver to the CNS with ABC? Are you going to lean more towards one type of modality versus others? And are you still going to continue to focus on large indications or are you going to venture into rare disease?

Yes, we are expanding our siRNA platform, as you said, and Eric said. We have a shuttle that can be used for multiple siRNAs. So -- and we have a really good screening process for siRNA, for potency and for minimal off-target activity. So, 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. But 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 tau 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 is really determined what we are doing.

Our next question comes from Graig Suvannavejh with Mizuho.

Thanks for this webinar, really informative and helpful. Just wanted to ask a few questions. One around 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 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 AL137 Phase Ib 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 part of the Phase Ib.

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%. trontinemab was able to reduce A-beta plaques by over 80% within 3 months and within 6 months, it was 90% to over 100%. So we want to be competitive with trontinemab. So the 90% is sort of a target based on trontinemab ability to reduce A-beta plaques within 6 months to this level and having, 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 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% A-beta plaque removal within 3 to 6 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 0, 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 human, 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-A-beta 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.

Our next question comes from Sean Laaman with Morgan Stanley.

This is Mike on for Sean. Two from us. First one, for the safety readout for AL137 in 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 reversible impacts to reticulocyte or hemoglobin signal be acceptable?

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 trontinemab, it seems as if the anemia was transient and reversible and they are continuing to Phase III. 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 some level of anemia.

That's very helpful. And then final question from us. On the development landscape and for other TfR-enabled shuttles in development targeting A-beta, our understanding is that some of those competitors maybe are using more of like an on-off switch in their modifications so that you can target A-beta but not target TfR in the reticulocyte. Do you think -- see this as viable? Is there any sort of commentary on the differences in antibody architecture and how that would plan out in terms of plaque currents?

You want to take this, Eric?

Yeah. So are you talking about the ability to engage Fc receptors when bound differently through TfR A-beta? Because I think that's what a lot of people claim, even back to the original Roche claim that the whole sort of 2+1 architecture with an anti-TfR binding domain on the end of the Fc, ablates Fc-gamma receptor binding. So this is partially true, but not fully true. And so certainly drugs with a full effector function that bind to the wrong epitopes on TfR, even in that two plus one configuration are still able to drive some level of reticulocyte depletion. If you're talking about on-off in terms of knocking out binding to specific Fc-gamma receptors, which is the other approach that's commonly being used. I mean, what we were trying to show is, especially because the clearance through pyroGlu A-beta is catalytic, right, you're targeting a small amount of the plaque and then you're engaging the innate immune cells to clear the rest of it, we really want to activate as many of the activating innate immune receptors on the microglia as possible, including Fc-gamma receptor 1, 2A, 3A. So that's, I wasn't exactly sure which of those two questions you're asking, but trying to answer both.

Yes, like any modification of the effector function yes, to reduce binding to one of the Fc-gamma receptors on immune cells is an efficacy risk. It's not clinically validated. And again, IgG2, IgG4 have different ability to bind to different Fc-gamma receptors and none of this work at all. Again, at a very high level, any modification or on and off modification of binding to any Fc-gamma receptors is an efficacy risk that will have to be resolved in the clinic in patients.

Our next question comes from Yaron Werber with TD Securities.

This is Steven Ionov on for Yaron. A couple questions from us. First is, given that AL050 is now partnered, how are you thinking about the 137, 164, and 062 programs in terms of whether to take them into the clinic yourself or to seek partnership? It sounds like the plan is to go it alone, but keep a lookout, but more color on that would be helpful. And then second, on the tau program, since you mentioned diranersen, do you think that there's a sweet spot for tau reduction based on that inverse dose response in the CELIA data? And is that informing your development for 164? And then also on the tau program, even though there was no ARIA, there were some adverse events, like some confusion, though potentially not related to the tau reduction. And do you think you can get cleaner safety than that ASO with an siRNA conjugate like a 164? I know that was a lot, but thanks in advance.

Yes, maybe I can take the second part, and Neil, if you want to take the first. Yes, we do think it's possible there is a bell curve for tau reduction, that too much tau reduction may be detrimental. But we do think that a lot of the adverse effect, both the confusion and the bell curve response, could be a combination of the intrathecal delivery and the use of ASO. ASO have inflammatory related adverse effects that siRNAs don't have, ASO with intrathecal delivery do have adverse effects, including confusion that are not target related. So I think at this point, it's really difficult to tell whether the adverse effects were related to the delivery method and the usage of ASOs, the nucleic acid technology versus a knockdown of the target. And we will have to explore that. We are targeting, I think at least 50% knockdown, we think that 50% is safe and we'll go from there to see where you get maximal efficacy.

Yes, Arnon, if you're finished, I'll take the more strategic part. Yes, so I mean, from a partnering perspective, we're obviously very excited about the partnership with Genentech and couldn't think of a better company to moving that program forward. And as Arnon had said, the proceeds from that deal do give us the flexibility to move these, the three programs we've talked about today, advance them ourselves and towards the clinic and we will continue to do so. I think on the side where we think about this more is around an indication specific. I think on the Alzheimer's side, we're definitely more comfortable with the clinical development and the movement of those programs into the clinic. But we will continue in the Parkinson's side as well. So again, just to say it very succinctly, we are planning to move them forward. We will talk to partners, and if partners are interested in these programs, we will talk to them. But our intent is to move these programs into the clinic.

I am showing no further phone questions at this time. I would now like to turn it to Neil Berkley for additional web questions.

Absolutely. Thank you. So, team, we do have a few questions online. There are two questions from Ananda Ghosh from H.C. Wainwright. First question is, he wanted to ask if we had any long-term safety 6 months plus with the tau-siRNA molecule, and also asked about the U-shaped, what our thinking about the U-shaped dose for BIIB080. I think Eric, maybe, or Arnon, I'm not sure exactly who you want to take the first one.

Yes, who I should take the first one. Yes.

Yes, for sure. We're in the process of planning and conducting the long-term safety studies for the tau program at this point. And for the question about the dose response on the BIIB080 that I think Arnon has already addressed. There are differences on the efficacy and also the safety. And we do think part of the safety does come from ASO, which we are more hopeful that the siRNA will resolve some of that.

Thank you. And there was another question from Ananda from H.C. Wainwright as well. It says, do we perceive that there's a problem with 100% effector function when bound to the transferrin? So, again, a question about the effector function, Eric.

I mean, I would say we don't see that as an insurmountable problem because that's our entire design criteria is to maintain the full effector function and then tweak the safety with other levers such as epitopes, such as the route of administration. So that is actually kind of our central design philosophy, is you need that full effector function.

Yes, we think that the strategy of sacrificing efficacy for perceived safety is a significant efficacy risk. As was shown repeatedly, you need extensive removal of A-beta plaques to start eliciting any clinical benefit. If you have a drug that is not able to fully remove A-beta plaques, you don't have a drug and the safety is becoming a secondary issue. So as Eric said, we don't want to sacrifice efficacy for safety, we found a solution where we can capture both of them with the unique epitope and the subcutaneous delivery and the low dose.

Great. Okay. So for the next question comes from Cathy Chen from City Therapeutics. Cathy asks, for our brain shuttle, we -- why did we use -- or why do we -- did we -- sorry, why you considered a half-Ab format versus a Fab? Because in her opinion, don't really need Fc portion for ADC modality. Fab should be equally efficient.

I will take that one. We tested them both head to head multiple times in murine and non-human primates, and the half-antibody format was superior across the board. So this is partially due, I mean, you don't need the Fc for effector function, but you still potentially need it for FcRn recycling to maintain your systemic levels. And also it makes the molecule large enough that you avoid renal filtration. So I would say there, one, we did see that, you know, other people are using the FAB. We tested the exact same molecule in Fab and mono-arm format and it's simply following the data, the half antibody format was superior in multiple, I want to say, in at least three different tests that we did.

I mean, the half-life of Fab is maybe one-tenth of the half-life of the sort of our shuttle. So, yes, you don't need to recruit immune cells, but you need the half-life or you want the half-life. And that's a significant advantage for dosing interval and to how much drug gets into the brain.

Great. Another question from another person at City Therapeutics discussing our RNA scope image of the 064 antisense in the frontal cortex suggests delivery almost exclusively to neurons and presumably endothelial cells. Is delivery truly this selective to neurons with little or no delivery to microglia or other glia cells?

It's either Eric -- Chou can take that or...

I can take that question. So we also examined the microglia and the astrocyte as well. And we do found the co-localization of the siRNA into microglia and astrocyte as well. But in the imaging we have shown, it's mostly just focused on the neuron.

Okay. And next question, Alex Culver from Monument Biosciences. Does optimization of the brain shuttling functionality of your transferrin antibody lead itself to peripheral tissue? And is there any plan to pursue non-CNS indications with the platform?

I would say that our platform has been highly, highly optimized specifically for brain uptake. We do look at peripheral uptake, but actually more in terms of safety. For some of these, we don't want to drive too much uptake and too much knockdown in non-brain tissues. I'll leave it up to Arnon whether we would ever do non-CNS targeting, but that's not what the shuttle is itself designed for.

Yes, it depends on the target. Like for siRNA, we do see siRNA entering peripheral tissues, but actually we don't see knockdown in this tissue. So, safety-wise, means we don't see meaningful modulation of peripheral targets. Means we have a whole range of brain shuttles, around 500-fold range of affinities and binding kinetics. And yes if we want to target a transferring media transport to peripheral tissues we can do that but so far we have not focused on this.

Just a couple more questions. One was about partnering strategy. We've already answered that. And then there was another question about, based on our cash position, do we have any plans to terminate the ATM offering at this point? And we, we have not disclosed or any or, or planning any changes for ATM at this moment. So, that is the list of questions I have currently, Arnon, so turn it back to you.

So thank you everyone for participating. If there are additional questions, feel free to contact us. And as you heard, the presentation and the recording of the webinar are going to be on our website later today, so feel free to reach out and see it again if you have questions or you have additional interest. So thank you again. This will conclude the webinar.

This concludes today's conference call. Thank you for participating. You may now disconnect.

Good morning, everyone. I'm Sean Laaman, Head of U.S. Mid-cap Biotech Equity Research here at Morgan Stanley, and welcome to Morgan Stanley Global Healthcare Conference. Before we commence, just to make you aware of some of the important disclosures. For those disclosures, please go to the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representative.

For this session, we have the pleasure to host Alector with their CEO, Arnon Rosenthal; CBO and CFO, Neil Berkley; and Eric Brown, Senior Director, Antibody Discovery and Protein Engineering. Welcome, gentlemen.

Maybe just some macro considerations to begin with before we dig into Alector. So how are you thinking about the rise in China-originated innovation? And is it changing your competitive positioning in your R&D and BD playbook?

So people are still suffering from cancer, from neurodegenerative diseases, from metabolic disorders. So in my view, innovation in medicine is helpful and essential regardless of where it is coming from. So I hope to see continuous innovation from the U.S. and from anywhere else in the world. And I think that innovation, sort of, promotes even more innovation. So I do see it positively.

For us, specifically, so far, the main competition or the main innovation from China is coming from immunology and cancer. Neurodegeneration is a more complex field with less clear pathways of like how to get approval, sort of, less obvious drug targets and drugs. So at this point, we don't see as much competition.

And based on the inbound interest that we have from large pharma, we are still, sort of, a significant force in innovative medicine for neurodegeneration. And we are actually trying to use the innovation in China instead of fear it.

So we work extensively with Chinese companies on the research stage level. We are looking at conducting possibly even clinical trials in China. I mean we are focusing on Alzheimer's disease and Parkinson's disease and available population in China is significantly larger and sort of, they are just starting now to get, sort of, updated with regard to clinical trials. So we are exploring clinical trials in China, and we are absolutely working with Chinese companies to advance our own programs.

Amazing. And second question on the macro. Are you implementing AI across your business? And if so, can you give an example where you've seen a benefit on cost, a benefit of function, maybe even a benefit on POS assumptions?

Yes, we are implementing AI in every aspect of the company. And at this point, the main advantage or benefit is efficiency. We think we can achieve more with lower cost and fewer people. So we are using AI to file our regulatory, sort of, applications. We are using AI to review business contracts. We are using AI to help design clinical trials.

So every aspect of the company is assisted by AI. At this point, I think it's fair to say that actual drug discovery, like actual innovation is still not there for AI. Like I don't think there are enough data to really predict like a new drug target means you can get help with like analyzing a lot of, sort of, genetic data and clinical data, but I still think you need the human mind to actually develop novel therapeutics. And so at this point, yes, we see AI as assisting with efficiency, but not really as much with actual innovation.

Yes. Thank you, Arnon. And last question on the macro before we dig into the heart of Alector. But even thinking generally or maybe specific to Alector, which policy variable do you consider the most important at the moment? Is it like the FDA?

Is it Medicare negotiations, MFN tariffs, global pricing? It's a lot to think about, but how do you generally think about those elements? And what's the most important?

As a company that, sort of, reentering the clinic in a few months, the most relevant for us is interactions with the FDA and -- sort of the FDA in a way, innovation or changes that we are really relying on the Modernization Act like that reduces the amount of animal usage, like basically, the main cost in entering the clinic nonhuman primate studies and the FDA is proposing alternatives to nonhuman primates and maybe shorter toxicity studies, and we are, sort of, relying heavily on that.

The second main thing, big thing is the surrogate biomarkers for clinical approval. I mean so I think we are spending significant amount of time developing and trying to validate biomarkers as a, sort of, to both facilitate the sort of clinical development and ultimately, clinical approval.

I think the FDA is relying more and more on biomarkers, the 3 anti-A-beta drugs that were approved were initially approved based on surrogate biomarkers, the beta amyloid imaging. I think more therapeutics are being approved based on surrogate biomarkers. So that's something we are looking at.

And the third thing is the increased frequency of interactions with the FDA. The FDA advanced multiple tools like INTERACT and pre-IND meetings that enables us to elicit feedback before we like -- design our clinical trials. So we are using this extensively asking the FDA what their expectations are, what would be accepted on them, both with regard to clinical design with starting doses with toxicity studies with how many species we need for our pre-IND program. So we are interacting very sort of constantly with the FDA to elicit information.

Wonderful. Thank you. Thank you, Arnon. So maybe some level-setting questions here to begin. So talk about the strategic shift to ABC. So a year ago, Alector had a Phase III program in FTD-GRN and a Phase II program in Alzheimer's. Today, need remains. The GSK collaboration is winding down. The next clinical start is expected in '27. So how would you define to investors what Alector is today?

So Alector has not really changed conceptually and philosophically. I mean we were started as a company that is dedicated for -- to cure neurodegenerative disorders to eradicate Alzheimer's disease and Parkinson's disease and Lewy body dementia and frontotemporal dementia. And our commitment to this mission remains. I mean we took 6 drugs to the clinic under a certain hypothesis that brain-specific immune checkpoints could provide effective therapeutics for Alzheimer's disease and other neurodegenerative disorders.

This specific hypothesis didn't pan out so far, but we are continuing now we are advancing enzyme replacement therapies for neurodegeneration, blocking misfolded proteins for neurodegeneration. So we are continuing to explore hypotheses for neurodegeneration with multiple different targets. We are advancing technology that enable delivery of enzymes, RNA, siRNA and antibodies to the brain. So yes, we are, means, we were a Phase III company.

We are a preclinical company now, but we expect to be in the clinic by early next year. So we will again become a clinical company. And our mission has not changed just the type of drug targets that we are advancing has evolved.

Okay. Can I just add one thing? Also, the team has been working on the Alector Brain Carrier for 7 years. This is not something that we started last year. This is something that's got a really deep foundation and very good science. And so we've been at the forefront of the blood-brain delivery space as well for many years now.

Yes, sure. It's a very important point. Thank you. Maybe the core value driver today seems to us the ABC platform. Can you give us a bit of a detail on the ABC platform? And you mentioned first patient dosing. Can you be a bit more precise on when that might occur?

Yes. I mean I think just to give a brief overview of the platform, as Neil said, we started working on this well over 7 years ago as a way to deliver our highly novel antibody targets into the brain. And as we've worked on it over the years, we've realized that it actually enables the delivery of so much more than just antibodies, which is how we built out our GCase program, which simply wouldn't work without blood-brain barrier technology.

And recently, we've pivoted towards siRNAs where really pairing siRNA and blood-brain barrier really gives you amazing therapeutic potential, like we've seen knockdown of up to 90% in certain targets in the brain. And then to get back to the last part of your question, we are looking to dose very early in Q2 in 2027. I believe Arnon might know a little bit more on the specifics, but the platform is much more than just the A-beta drug.

Sure.

Yes. So we are -- we have 5 drugs that we are advancing to the clinic now. The most advanced one is an anti-A-beta antibody, which is brain enabled that is expected to be in the clinic by April next year. We have tau siRNA, which is brain enabled and there is sort of some supportive data from the Biogen-Ionis clinical trial.

We have tau siRNA, which is brain enabled. Again, that's tau -- sorry, alpha-synuclein siRNA, which is brain enabled. Alpha-synuclein is the hallmark misfolded proteins in Parkinson's disease. And we have enzyme replacement therapy for Parkinson's disease and Lewy body dementia. This is a GCase, which is a lysosomal enzyme that's mutated in a large percentage of Parkinson's patients and Lewy body dementia patients.

Sure. Maybe just on the resourcing of the platform. So you reduced workforce significantly. So what capabilities sort of remain in-house? And do you have the team in-house to move AL137 through?

Yes, we absolutely have the capabilities. We do -- we did reduce the team, but that was actually an opportunity for us to implement a lot of AI tools to really compensate for the reduction in headcount. We retained all our basic R&D capabilities like in drug discovery, sort of antibody and protein engineering, preclinical, nonclinical studies.

We have a clinical team that's advancing AL137. So we are a more nimble team, but we didn't really lose any core capabilities. And we are -- because of our smaller size, we are really implementing more AI to substitute for headcount. A lot of things that were done manually are now done through sort of computerized system.

For example, we had a very large clinical operation team. We are sort of supplementing it with AI. And we are using a lot of outsourcing, including from China to really substitute for sort of smaller size. So we think that with regard to capabilities, we will find alternatives to the larger headcount.

Sure. And with AL137, so first patient dosed early next year, how should -- or how would you phrase the data map and milestones looking forward over the next few years? What would it look like?

So we are going to start with healthy -- like again, this is an anti-beta amyloid antibody that's brain enabled. It has -- it recognizes the so-called pyroglutamate epitope on the beta amyloid peptide, which we think is the most toxic and aggregating sort of stimulator version of A-beta. We have a very potent blood-brain barrier shuttle that brings a lot of drug to the brain at very low dose.

Our brain shuttle because of the unique site that it binds the transferrin receptor reduces the anemia risk. This enables us to use what's called the full effector function, full ability to recruit immune cells to remove beta amyloid plaque. So we are targeting best-in-class drug that's going to be delivered subcutaneously once a month. And we are going to start seeing data in healthy volunteers by sort of Q2 next year and the healthy volunteers data here will show us pharmacokinetics.

This means we will have exposure data in the CSF, which in our case based on nonhuman primate data, reflects very well on brain exposure and we will show multiple safety features. Like anemia is a major risk factor for the brain shuttle that everyone is using.

We are going to look at anemia. We are going to look at infusion reactions that competitors like gantenerumab are suffering from. We are going to show that subcutaneous delivery does lead to efficient exposure. So we'll have by midyear next year, we will have a really good package of pharmacokinetics and safety. And right after that, we are going to move to patients. With brain shuttle, as was shown by, again, the Roche antibody, within 3 months you start seeing significant impact on the Alzheimer's pathology. So by PET imaging, you should see reduction in A-beta plaques.

By serum and CSF biomarkers, you should see reduction in, for example, p-tau217, which is a reflector of A-beta pathology. We will be able to show minimized sort of effect on ARIA and other safety features. So by the end of 2027, early 2028 we will have a good package of clinical benefit based on biomarkers and safety package.

Sure. And just to maybe pinpoint to investors, what's the strongest translational evidence that you have that you can deliver meaningful brain exposure in a safe manner?

I mean the main -- means we have conducted IND-enabling toxicity studies and pharmacokinetic studies in nonhuman primates. We see with subcutaneous delivery at low dose, single-digit dose. We see brain exposures that significantly exceed what in our calculation was reported by any other either naked antibody or antibody with brain shuttle.

So we see several fold higher brain exposure. We see a very manageable hematologic effect, and we don't see adverse effect associated to -- with anemia. And again, our data suggests that a monthly subcutaneous delivery will be more than sufficient to get maximal brain exposure.

And just to chime in a little bit on the platform side, beyond the A-beta antibody, if we look at our enzyme or our siRNA program, because we're able to utilize an effectorless Fc because it's not part of the mechanism, we've dosed at very high levels in nonhuman primates up to 250 mg per kg, and we've seen no effect on hematological parameters. So there's an additional like layer of safety on the platform.

Sure. That's very important. I guess thinking about the platform more broadly and your competitors. So donanemab -- Denali's approval validates TfR and mediated transport, but also sets a pretty high competitive bar in our view. What does ABC do differently? Is it transport efficiency, brain distribution, dosing manufacturability or what we just discussed, the hematologic safety?

I would argue that the Denali approval sets really a good standard for the field, but it's also, I would say, a relatively low bar in a sense, they picked a really good area to start with, right? So it's a rare disease where you can tolerate not a great route of exposure.

So they're doing weekly IV, right, because they need that to drive enough enzyme in. Because it's an enzyme replacement therapy where there's no copy of the native enzyme, you only need to get delivery of a very low absolute amount of enzyme into cells in the brain to see a large therapeutic effect. So it really is a great beachhead drug. But if we compare our drugs to theirs and what's been reported in the literature, the main difference that we see is much higher absolute level of brain uptake.

So we've seen this both with antibody cargoes, with siRNA cargoes. With their enzyme cargo, they don't actually show the absolute level of brain uptake, but we expect based on what we see, which is around or higher than 10 nanomolar exposure in the brain with our GCase drug that we're also seeing significantly higher uptake of an enzyme replacement drug. And for anything other than an absolute knockout, like for the GCase, we're looking to actually replace an enzyme that is half of the normal activity level.

So rather than just getting a tiny amount in to catalytically remove a highly increased substrate, we need to actually double the amount of therapeutic enzyme that's in the native body. And we've shown that we can do that in the brains of nonhuman primates. So I'd say first and foremost, the absolute level of brain uptake that we're able to drive and especially the level of uptake we're able to drive in the cells is one of the main drivers.

Sure. And AL137 targets pyroGlu form of A-beta, with potential monthly sub-dosing. Can you comment on the differentiation on target specificity and on administration frequency?

Yes, that's a great question actually. I mean the 2 anti-A-beta antibodies that are on the market now one of them is targeting the pyroglutamate from Lilly donanemab and the other is targeting soluble protofibril like the terminal of soluble protofibril. This is lecanemab.

They show generally similar efficacy, donanemab, which targets the pyroglutamate incrementally show a deeper removal of A-beta plaques, faster removal of A-beta plaques and incrementally possibly better clinical outcome. So we chose the pyroglutamate because of the comparative clinical data of donanemab and lecanemab.

The other advantage of the pyroglutamate is that there is no pyroglutamate version of the A-beta peptide in the periphery. So there is no what so-called sink effect. The antibody doesn't get stuck in the periphery. It all goes to the brain. So we think that at lower dose, you can get the same efficacy.

The subcutaneous delivery and monthly doses are really related to the potency of our antibody and to the potency of the brain shuttle. Once again, as Eric said, we have very potent brain shuttle that enables several fold higher exposure in the brain compared to competitor, and this really enables us subcutaneous delivery and monthly dosing. And we think that the pyroglutamate target will be very effective in removing A-beta plaque.

Wonderful. And what do you think 137 would need to demonstrate to be commercially relevant versus approved anti-amyloid antibodies?

Is it materially lower ARIA monthly subcut administration, the better plaque clearance or some combination?

I think to a large degree, all of the above. I think you need to have extensive removal of A-beta plaques. We know based on the first generation of our antibodies, donanemab, lecanemab, aducanumab, gantenerumab, and crenezumab, that partial removal of A-beta plaques does not lead to clinical benefit at all. The Roche antibody gantenerumab reduced A-beta plaques by 60%, 70%, was not associated with any clinical benefit.

You need to reduce A-beta plaques by 80%, 90%, 100% to see clinical benefit. So extensive removal of A-beta plaques is really essential. One of the main sort of predicted benefit of brain shuttle-associated anti-A-beta antibodies is reduction in ARIA or elimination of ARIA, so we have to show that. You have several questions around the ARIA. This is actually a great question.

The hypothesis is that with brain shuttle, the mode of entry of the drug to the brain will eliminate ARIA, but so far we have only one example that with the Roche antibodies, so we actually have to see if that's the case. So we need to show extensive and rapid A-beta plaque removal. We need to show no ARIA.

I think the subcutaneous delivery will be significant advantage. The Roche gantenerumab is still being delivered with IV infusion that require infusion centers, and it's much less convenient and scalable. So being able to deliver drugs subcutaneously, likely at home once a month, would be a significant advantage. Also minimal anemia or hematologic adverse effects, which are the side effects that comes with the brain shuttle technology. So I think you'll have to be competitive, you have to show all of the above.

Sure. Okay. Moving on a little bit to just some financing and strategic questions. So you finished the period, I think, with around $170 million cash on balance sheet. Does that get you to -- through the proof-of-concept data? Or does it only get you to the initial dosing?

No. I mean, we -- our current capital allows us to get to into patient dosing, the patient trial.

Got you.

And we have a lot of flexibility, financial, like we announced that, yes, we have enough resources through 2027, but we have a lot of flexibility of like how we use the resources, like how aggressively we advance other programs. And also, we have a lot of inbound, sort of, partnering interest that could or would bring additional resources. So we think we will be able to go to absolutely proof of concept in patients with the resources that we have and we'll gather.

Right. So that leads into the next question, which is, is the financing strategy to partner the ABC platform, partner individual assets or advance 137 independently and raise against early human data.

Maybe I'll take that. I mean I think we look at -- the way we look at partnering is that we're asset focused on partnering. We do not typically look at broad platform deals and monetization of the platform. We're in the fortunate situation to have multiple assets. And across the board, there are companies who are interested in all the different assets we're doing.

We are very focused on moving A-beta through to clinical proof of concept ourselves. And we are open to discussing other programs and partnering opportunities. We're very active in the partnering space and hope to be able to close one of those in the short term.

Got you. I look forward to that. Moving a little bit on to some of the follow-on platform programs. And AL164 is a modified version of AL064 moving into IND-enabling studies. Why the reformulation? And can you talk about the changes you've made that increases your confidence in the program?

Yes. So AL064, in a sense, was a proof-of-concept study that we could deliver and significantly knock down tau in the nonhuman primate brain. Between AL064 and AL164, we simply made some tweaks to the chemical modification on the siRNA using well-validated chemical modifications that are designed to increase the stability of the siRNA. And this gives us really good confidence because already with 064, we were seeing significant knockdown of CSF tau that was lasting up to 70 days post administration.

And now with stability enhancing mutation -- clinical modifications and also we're seeing stronger initial knockdown for AL164, especially with subcutaneous administration than we saw with AL064. So putting those pieces of data together, it gives us really good confidence that we'll have both high level of absolute knockdown and also a sustained knockdown of both tau mRNA and tau protein.

So we now have data with 167 in nonhuman primates that's sort of on our -- on the corporate deck that we just posted. And yes, with sort of 164, we do see over 70% knockdown of tau mRNA with subcutaneous delivery. And we think based on our other data that it's going to be durable for at least 3 months -- so we have a potent what means you don't see any safety signals. So we think we have a potent safe and durable anti-tau drug that would be very -- that can be delivered peripherally subcutaneously and could be very competitive with the Biogen-Ionis drug.

Sure. It sounds really interesting. Maybe moving on to AL050, showed increased GCase activity in NHPs with no hematologic findings. I believe others have ETV GCase program too like Denali. So what's the differentiation? And what is the IND timing?

So I'll take the differentiation part. So we extensively engineered our GCase enzyme to have both greatly enhanced activity, like more than 50-fold increase in activity over the native enzyme, but also greatly enhanced stability, so also 50-fold increase in stability over the wild-type enzyme.

And then we had to search and pair it with the exact right anti-TfR ABC and really only -- we've conducted multiple NHP studies. It was only when we paired the most active GCase with the most optimized TfR that we were able to see that 100% increase in activity in NHP brain. And to my knowledge, Denali has not shown NHP data showing that level of -- I haven't actually seen any NHP data for their program. And one thing we have seen working over this program for 7 to 8 years is that really the translation from mouse to NHP is the biggest hurdle.

There are a lot of things we tried that work in the mouse and show great data and then you put in the NHP and they just don't show the same level. So we think having that level of data in nonhuman primates is what makes us really confident we can move this program forward.

Yes. So basically, our main differentiation is that our drug actually works in nonhuman primates. That's a good predictor for human, and we are not aware like, multiple companies who said Denali, Roche reported data in rodents. Rodents are much easier to cure than nonhuman primate and human. So the transition from rodents to nonhuman primate is something that we were the only one who were able to demonstrate as far as we know.

And beyond 137, which program offers the path -- the fastest path to demonstrating that the ABC platform is repeatable versus a single asset story?

Yes. After the 137, the second most advanced drug that we have is the siRNA. So we have 2 Alzheimer's programs that are advancing to the clinic. For both programs, there are really good imaging and biomarker tools that with a fairly small sort of cohort of patients with a fairly short time frame of 3 to 6 months, you can start seeing sort of efficacy sort of for A-beta, the PET imaging for A-beta, the soluble biomarkers p-tau217, A-beta 40 to 42, means can give you really good indications of efficacy. For tau, the tau PET imaging and multiple measurements of total tau and phospho-tau can give you indications of efficacy. These two Alzheimer's programs, I think by next year, we will start hopefully seeing some data that will indicate that both the drugs themselves and the technologies are working. Beyond that, we have the two Parkinson's program.

One is the enzyme replacement therapy, and the second is the alpha-synuclein siRNA that also is advancing. For example, for alpha-synuclein siRNA, we see 94% knockdown of mRNA with subcutaneous delivery, which is very profound. We think we have, again, two drugs for Alzheimer's disease, two drugs for Parkinson's disease that look very promising, and they're all advancing.

Fantastic. So you've got 5 programs advancing towards the clinic. 137 will get data next year. You maybe some differentiation there with subcut dosing, hematological safety, and we look forward to the safety and maybe some efficacy data at some point. You've got cash runway, $170 million finished the quarter, gets you through '27.

We'll get you through proof-of-concept data. You've got good pharma interest on potential partnering opportunities across the pipeline. Now I've come to the end of my questions.

Is there anything that I've missed or anything I should have asked that I didn't or any message that you'd like to leave investors with?

I think you summarized it really well. But yes, we have -- I think that some investors define us that we are still in the penalty box because of our past portfolio. We have now a completely new portfolio of drugs that's really a much more validated like the risk associated with anti-A-beta antibodies, tau siRNA, alpha-synuclein siRNA, GCase.

These are all validated programs based on human genetics based on past experience. We have great technology to transport the drug to the brain. So I think our next wave of drugs is much more likely to succeed. We have the resources and the tools and the experience to get it done. And I think people still underestimate the value that we can create in the next 2, 3 years.

Wonderful. Well, that might be a nice place to park our conversation. But thank you for attending. I appreciate you coming.

Thank you.

Thank you.

Great questions.

Welcome to the Cantor Global Healthcare Conference. I'm Pete Stavropoulos, a biotech analyst with Cancer. With us, we have Alector, and I'm pleased to introduce Dr. Arnon Rosenthal, CEO. Let's start off with an introduction of yourself, followed by a snapshot of the company and just sort of touch on the milestones that are going to shape the company over the next 6 to 12 months or 12 to 18 months.

Great. Thank you for hosting me, and welcome, everyone. That's one of the more crowded fireside chat that I've been at. So Alector is a sort of neurodegeneration focused company. We've been around for a decade now. We've taken 6 drugs to the clinic. We are now developing a portfolio of antibodies, enzymes and nucleic acid therapeutics that are propelled by our blood and barrier technology. Our most advanced drug is an anti-beta antibody that we think combined like possibly best-in-class features. It's recognized the pyroglutamate epitope on the Abeta that seems to be the most potent epitope for A-beta plaques. It has a potent blood and barrier technology that uses the transferrin receptor as a Trojan horse, using a unique epitope that maximize brain penetration and at the same time, significantly reduce the anemia risk that's associated with transferrin-based brain shutters.

It has a full effector function that would ensure complete removal of A-beta plaques. And because of its potency, it's targeted to be delivered monthly subcutaneous. And this drug is designated to be in the clinic by April next year. Our next set of drugs are brain-enabled siRNA Programs. We have tau siRNA that can knock down siRNA and that knock down tau mRNA in nonhuman primate by over 70%. Again, it's going to be monthly subcutaneous delivery. And we have an Alpha-Synuclein siRNA that knocked down mRNA in nonhuman primate by over 90%. Again, it's going to be subcutaneous every 3 or 6 months delivery. And we have a GCase, which is a lysosomal enzyme replacement therapy. GCase is the most prominent genetic mutation that leads to Parkinson's disease and Lewy body dementia. We are the first, I think, and as far as I know, the only one who are able to engineer a very unstable enzyme to make it 50 to 100x more stable and linking to our potent blood-brain barrier technology, enabling peripheral delivery of this lysosomal enzyme.

So we have a portfolio of, again, enzymes, antibodies and nucleic acid therapeutics that are going to the clinic.

All right. Can you just give us an overview of your ABC platform? What makes it -- that may make it able to address the hurdle of the blood-brain barrier as well as target selection for transporting therapeutics across the blood-brain barrier and modalities that can leverage it?

So our platform is based on the transferrin receptor. As you know, the transferrin receptor is expressed on the blood-brain barrier. The brain requires iron for functioning. And we, as multiple other companies are using the transferrin receptor that normally transport iron from the blood to the brain as a Trojan horse to deliver drugs to the brain. We are using this shuttle, again, to deliver antibody therapeutics, primarily anti-Abeta antibodies, enzyme therapies, GCase is an example, and multiple nucleic acid therapies like we are, again, as I mentioned, developing tau siRNA, Alpha Synuclein siRNA, NLRP3 siRNA and is a major anti-inflammatory or inflammatory mediators in neurodegeneration as well as multiple other targets.

So we tailored the technology for each drug modality. Although we are not the only one who are using transferring as a Trojan horse, what's unique with our technology is the tunability means for -- again, for each drug modality, we are using different shuttle structure, different affinity. And most fundamentally, we are using a unique epitope from the transferring receptor that again maximize brain penetration while minimizing the intrinsic side effects associated with transferring receptor, which is the anemia specifically the epitope that we are using on the transferring receptor significantly reduces the ability of the drugs to simultaneously bind reticulocyte and immune cells. So anemia with this technology is caused when you have a drug that on one end, bind the transferring receptor and on the other hand, has the ability to recruit immune cells to the drug.

You need it because in the brain, for example, when you want to remove A-beta, you want that drug to bind the beta from one side of the antibody and then recruit immune cells to it or remove the A-beta plaques. But the same mechanism also recruit immune cells to reticulocytes and that's what causes the anemia.

The specific [indiscernible] epitope that we are using largely prevent that or avoid it when the drug binds reticulocytes, its ability to, at the same time, recruit immune cells is significantly reduced. At the same time, when the drug binds Abeta plaques in the brain, it retains full ability to recruit immune cells. So we have a full functionality with regard to removal of Abeta plaques, but significantly reduced adverse effects. So what's unique in our technology is really the epitope. The epitope enables us to use a much larger range of affinities, which enables optimized brain delivery for different drug modalities. So we think we really have proprietary good technologies, again, that can deliver antibodies, enzymes and nucleic acid to the brain at very high potency and safety.

So let's get into your amyloid beta program, lead candidate is 137, which is, as you mentioned earlier, it's going to enter the clinic in April. Let's just go into the details of this molecule and why you believe it's designed to overcome shortcomings of the first, second and third-generation amyloid betas.

So the first generation of anti-Abeta antibodies, as you know, are antibodies without brain shuttles. These are lecanemab and donanemab. And both of them shows basically remove A-beta plaques over a period of 18 months. They show modest clinical benefit of slowdown in cognitive decline of like 25% to 30% over 18 months. Until very recently, they were delivered by intravenous application, which is not very convenient requiring infusion centers. And the main safety issues with this type of drugs is the ARIA. Basically, the antibodies likely bind Abeta plaques on blood vessels, recruit immune cells to the blood vessels, the immune cells, reduce inflammatory mediators cause leakage of blood vessels, and that's what caused basically brain inflammation and blood leakage that's a major side effect of the first-generation drug.

So Roche developed a second-generation anti-Abeta drugs with a brain shutter. This brain shutter-enabled drugs remove Abeta Plaque at least 3x faster than the naked antibodies. It removed the Abeta Plaque more extensively. The ARIA-related side effects largely disappear likely because of the mode of entry of the antibody drug to the brain. But instead, what they now see is cases of anemia and significantly higher cases of infusion reaction. And the drug is still being delivered intravenously. And because of the infusion reaction, patients require IV steroid pretreatment.

So even though the drug shows significantly increased potency, it's still being delivered IV, which is not convenient, and it is associated with anemia and infusion reaction related adverse effect, to overcome these issues, there is, in a way, a third-generation group of drugs that Denali, AbbVie, Korsana are developing, where in order to reduce the anemia risk, they crippled the ability to recruit immune cells. So they basically reduce the potency of the antibody to bring immune cells to the target. This indeed leads to better safety like there is reduced anemia, but the same mechanism that recruit immune cells to reticulocyte is also required to recruit immune cells to A-beta plaques.

And as a result, you basically increase safety, but you significantly reduce efficacy. We didn't really want to pay in efficacy for safety. So that's why we really developed a unique epitope on the on the transferrin receptor that enables us to really retain a full ability to recruit immune cells with significantly reduced anemia risk. So we think we have the best of both worlds. We have maximal potency because we have a full ability to recruit immune cells, and we have a very manageable safety because our epitope on the Abeta -- on the transferrin receptor enable like significantly reduced anemia.

So again, the potency of our antibodies will enable very low dose subcutaneously monthly delivery. The unique epitope, we think will reduce both the anemia-related adverse effects and the infusion reaction related adverse effect. And again, sort of the unique epitope on the Abeta we think will be significantly more potent or possibly more potent than trontinemab.

So 137 targets PyroGlu3, donanemab derisked the target. But what's your rationale for choosing that versus another A-beta species -- sorry, epitope.

It's a great question. Like if you look at the naked antibodies like if you compare donanemab to lecanemab, donanemab, which binds the pyroglutamate versus lecanemab, which binds like general and terminal aggregated Abeta. -- sort of donanemab reduced Abeta faster and incrementally showed some better clinical outcome. So it suggested that sort of the pyroglutamate, which donanemab is targeting is a better target. The pyroglutamate is only present in A-beta plaques -- and in fibrils and protofibrils, it's not present as part of like monomeric Abeta. So we think it's specifically targeting the toxic versions of A-beta, which tends to aggregate and it spares the monomeric Abeta that's not toxic and it's present also in the blood or in the serum. So targeting this epitope, I think, will lead to faster A-beta plaque removal. It's not going to be sequestered in the periphery because this epitope is not present in the periphery. So overall, I think that sort of it's a better epitope. It's a good question whether the brain shutter will really nullify this differences.

All right. Going into some of the details of the exposure levels in preclinical models, sort of what gives you confidence that you tune the affinity of a transparent binding module for optimal delivery to the brain?

Yes. So we sort of we compare the whole range of affinities and we compare to what's published in the literature and what we can be [indiscernible] from the trontinemab exposure. And from what we can tell from nonhuman primates, our technology can deliver several fold more antibodies to the brain compared to any competitor that published data in nonhuman primates. If we look at brain exposure, if we compare trontinemab to our drug, we see significantly better brain exposure sort of half the dose of trontinemab when we deliver subcutaneous versus the IV delivery of trontinemab. So basically, based on multiple nonhuman primate studies and based on multiple modeling that we have done and based on published information that we have collected -- the epitope that we are using, the affinity that we are using, the binding kinetics that we are using to the Transferrin receptor leads to several fold better brain exposure compared to other drugs that we know.

All right. So the epitope, the transferrin binding module binds to may impact safety profile like we discussed earlier. Preclinical data, what it sort of suggest about 137 in terms of safety?

Yes, we see if we compare sort of the same affinity of binding to transferrin receptors, what we call the exposed epitope that Roche and Denali and Korsana and AbbVie are using to our masked epitope, we see that at the same affinity, our epitope is significantly safer. Like in nonhuman primate, the companies that are using the exposed epitope means we see significant reduction in red blood cells, significant reduction in hemoglobin. We don't see it with our mask epitope. So we think that our epitope is significantly safer. And this enables us to go to significantly higher affinity of transfer binding, the higher affinity enables, again, several fold better brain penetration. So basically, we can gain much better brain penetration with much more manageable safety profile.

Part of the target product profile is a monthly low-dose subcu. What are the properties of the antibody that will facilitate this? And how can a low dose impact the adverse event profile versus other transparent binding platforms?

Yes. the properties of the antibodies that enables that, again, it's a very high potency brain penetration and sort of the general drug features, it's easy to concentrate it to at least 150 mg per ml, which enables subcutaneous delivery. means yes, we calculate that sort of with 2 ml injection, we can reach significantly above the calculated efficacious dose. So the potency of the antibody, the ability to enter the brain at high concentration and the ability to concentrate the drug that's pharmacokinetic feature is sort of ensuring that we can deliver it subcutaneously. And I think that a significant portion of the side effects, for example, the anemia-related adverse effect are associated with what's called the Cmax, the highest level of the drug can reach in the serum. When you inject intravenously, you reach much higher level of sort of maximum level of drug in the serum compared to subcutaneous injection. There is at least tenfold in the -- what's called Cmax or the higher level of antibodies that can be reached.

So subcutaneous delivery as a result, is much safer. You don't reach higher level that elicit adverse effects. You reach a much lower like chronic dose. And so in the periphery, our drug doesn't reach high dose and it's therefore, much safer. But in the brain, the exposure is much better than IV delivered drugs. So we have a really good combinations of low exposure in -- relatively low exposure in the periphery that mitigate adverse effects and very good exposure in the brain that facilitate efficacy.

Right. So you are starting a Phase I in Australia in April. How wide of a dose range will you be evaluating? And is it going to be IV or subcu?

It's -- all our doses are going to be subcu from the very beginning, like in healthy volunteers. And then in patients, we are only delivering subcu, like based on our nonhuman primate studies and modeling, we are quite certain that we can reach efficacious dose very easily with regular subcutaneous delivery means we are planning to test at least like 4 dose cohorts, both in the healthy volunteers and then in the patients that are like threefold increments. And again, we have extensive modeling of what we consider to be the efficacious dose. So it's going to be 2 doses from each side of the efficacious doses like threefold increment.

Okay. So hematological AEs will likely be the key event that you'll be looking out for. Were these AEs observed in other Phase I [indiscernible] studies for other platforms? And what percent of subjects experienced, if so, these AEs? And what will you find sort of as an acceptable level?

So adverse hematologic events are considered if you reduce your red blood cell count or hemoglobin, I think, by more than 15% or 20%. We have not seen it in our nonhuman primate studies we see transient reduction in reticulocytes that recover very quickly and do not lead to adverse events in red blood cells or hemoglobin.

In the clinic, sort of Roche with trontinemab reported somewhere between 10% and 20% anemia rate in their sort of Phase I and Phase Ia or 2. And I think that sort of they argue that it's manageable. The fact is that in the clinical trials in all the Alzheimer's clinical trials, there is significant underestimation of the anemia rate. In Alzheimer's patients, the anemia rate is about 30%. In the clinical trials, the anemia rate is about 15%. A lot of the more severe anemia patients are being excluded as part of the general sales exclusion criteria. So I think the clinical trial really underestimate the issue around anemia. And I think once Roche or other companies going to the real-world treatment, the anemia rate could go significantly higher. So it is an issue even though in the clinical trial setting, it is manageable.

Key gating factors to us actually initiating the Phase I?

Yes. The only key gating factor for us now is completing the manufacturing. We have a very good manufacturing process of very high yielding cell line. Again, we are able to concentrate the drug to high concentrations that's very amenable to subcutaneous delivery. So it's just the time that it takes to manufacture clinical drug to start the clinical study.

Then you are planning to move into a Phase Ib MAD study in Alzheimer's patients 3Q. Is that correct?

Yes.

And then what's the overall design?

Again, it's going to be 4 cohorts. It's going to be 15 patients per cohort. It's going to be placebo-controlled. It's going to be at least sort of 6 months treatment with open-label extension. It's going to be monthly dosing, and we are going to frequently look at Abeta plaque reduction with PET imaging every sort of 2 or 3 months. We are going to look at multiple serum and CSF biomarkers, including p-Tau217, that's a good indication of Abeta plaque burden. We are going to look at anemia rates, infusion reaction rate, ARIA rate. So with this Phase Ib will have, I think, a pretty extensive package of biomarker and imaging-based efficacy and a pretty good safety analysis.

So you said it's a 6-month study. Will you go to completion before we start seeing data? Or is it possible?

No, we are going to, I think, report data as an ongoing basis as we generate them.

Can you just remind us how quickly trontinemab reduced plaque and changes in 217 levels?

So Roche reported that after 2 injections, almost 40% of the patients went down to basically below A-beta positivity by PET imaging by 6 months, I think over 90% of the patients were below Abeta positivity. So within 3 to 6 months, you should see significant -- statistically significant reduction in A-beta plaques. For tau, even after the first injection, you start seeing reduction in -- sorry, in Abeta phospho-tau -- sorry phospho-tau217, even after the first injection, you see reduction in phospho-tau. After 6 months, trontinemab reported, I think, 51% reduction in phospho-tau. So we do expect to see reduction in phospho-tau within 3 to 6 months period.

All right. So the first study you had is in Australia. The second one, Phase Ib will be.

The Phase Ib will be in multiple sites in the U.S. I just faster and easier to do the healthy volunteers in Australia. I think 50% to 70% of the Phase I are now conducted in Australia. So Alzheimer's patients in Australia is a relatively small population. There are 20 million people in Australia. So it's harder to find patients. So we are going to go back to the U.S., although we may still -- we conducted 2 Alzheimer's trials in the U.S. in the past. So we may keep some sites in Australia, but the main -- the bulk of the trial will be in the U.S.

Okay. So the last several minutes, let's just touch on the tau knockdown program. You generated a lot of preclinical data. So what are the sort of key data points that you'd like to highlight about this program?

Yes. It means we have generated data means we can show -- we showed in nonhuman primate that by subcutaneous delivery, we can reduce tau and messenger RNA by 70% to 80% in every brain tissue that we analyzed. The drug appears to be generally safe, means the effect is durable, means we have measurement so up to 3 months and the reduction in tau is sustainable. So we think that we have a durable potent drug that can be delivered subcutaneously, peripherally. And I think it's going to be a very competitive tau drug. As you know, Biogen and Ionis have reported ASO that's sort of delivered intrathecally. They did show significant reduction in tau by PET imaging, by soluble biomarkers.

I think they show consistent positive clinical trends. It didn't reach statistical significance and the higher dose did not do as well as the lower dose. So there are some questions on the trial. But I think overall, in my view, it was a positive study. It's in my view, possible that the intrathecal delivery was associated with some of the confusing data and maybe the less than stellar efficacy results. Intrathecal delivery was shown to be, in some cases, associated with confusion that's really the counter indicative for Alzheimer's disease. So it's possible that, again, peripheral delivery of our siRNA that's homogeneously distributed throughout the brain does not lead to intrathecal delivery leads to could lead to significantly better efficacy and safety. So I'm very optimistic about the program.

When can we expect the clinic?

Yes, by next year, sometime next year.

Okay. In the last 2 minutes or so, how are you thinking about BD? Are you looking at partners to partner on specific candidates? Or are you looking for.

Yes. We are -- I mean there is a lot of inbound interest in partnering. We are focusing on actually partnering our Parkinson's programs. We didn't talk about our GCase enzyme replacement therapy. We just mentioned it at the beginning and maybe then tau siRNA that's brain enabled. It means, again, we just put a new corporate deck on our website, we show that by subcutaneous delivery, we can knock down the Alpha Synuclein by 95%, 94%. It's very potent. We have very potent Alpha Synuclein siRNA. We have, I think, best-in-class GCase enzyme replacement therapy, and we are focusing on really partnering these assets and there is a lot of interest, and we are targeting to have a partnering deal by the end of this year.

And the Alzheimer's programs we are retain. I mean, Parkinson's disease is a great indication. There are like 10 million Parkinson's patients worldwide, but the clinical trials are a lot more complicated. There are no imaging tool. There are no biomarkers. So you really need to run complete clinical trial and large pharmas are better set to do that. Alzheimer's now the imaging tools, the biomarker tools are much more established and look for with a small cohort with a short clinical trial, you can look at that.

So if we're sitting here 12 months from now, what would you like to see your key value-creating [indiscernible] have been over the past year?

Yes. we will have complete data of our anti-beta antibody in healthy volunteers, which show exposure in the CSF and room, which show safety, again, anemia, infusion reaction. So we'll have pharmacokinetics and safety in healthy volunteers. We will start having data in patients like the first or second cohort that actually should possibly start showing clinical or biomarker-based clinical outcome with PET imaging and with soluble biomarkers. So we'll have a complete data set in healthy volunteers and then initiation of data in patients.

We will advance tau siRNA Alpha Synuclein siRNA and GCase toward the clinic next year. And so we'll have, again, 4 programs that are either in the clinic and patients or going -- or becoming very close to the clinic.

Well, I would like to thank you for participating in the Cancer Healthcare Conference. I always love seeing you. Really excited to see the ABC platform go into the clinic and see those first results next year.

Thank you.

Yes. So looking forward to watching all the progress.

Thank you.

Hello, everyone. I'm Pete Stavropoulos, biotech analyst at Cantor with another webinar on the blood-brain barrier crossing technologies. It's an exciting time for the field. The blood-brain barrier has been a bottleneck in CNS drug development, preventing many promising therapeutics from reaching their targets in the brain.

However, a wave of delivery platforms designed to actively shuttle large therapeutics across the barrier is gaining momentum. These platforms are already demonstrating potential to dramatically expand the reach of CNS drug development, and they will lock a lot of value from neuro indications.

We're excited to have with us Alector, who has developed the Alector Brain Carrier, a differentiated blood-brain barrier crossing platform, developing a pipeline of brain penetrant therapeutics. With us, we have Arnon, the CEO; Giacomo the CMO; Neil, CFO/CBO; and Eric Brown, Director of Antibody Discovery and Protein Engineering.

So with that, please give a brief introduction of yourselves as well as a snapshot of where Alector is at the current moment.

So thank you for hosting us, Pete, and welcome, everyone. Alector was created with the mission to eradicate neurodegenerative disorders that constitute about 10% of the general population and over 25% of individuals over 65. So we are focusing on large diseases like Alzheimer's disease, Parkinson's disease, Lewy body dementia as well as small diseases.

And we are integrating in-depth biology to understand genetically validated target, and we are developing technology, as Pete mentioned, blood-brain barrier technology specifically to develop drugs.

At this point, we have 5 drugs that we are advancing either in the clinic or advancing to the clinic. We have a Phase II drug, which is an antibody that elevates progranulin. Progranulin is a risk gene for Alzheimer's disease. So there is significant genetic validation. This is a Phase II drug with interim analysis will be read in the next few weeks. It's a placebo-controlled double-blind trial with a completely novel mechanism of action.

We have a brain-enabled anti-A-beta antibody that we are going to discuss in more detail during this seminar.

We have brain-enabled Tau siRNA program. We have brain-enabled alpha-synuclein siRNA program, and we have brain-enabled GCase enzyme replacement therapy for Parkinson's disease and Lewy body dementia.

So most of these therapeutics were not enabled until we developed the blood-brain barrier technology. And our blood and barrier technology is tailored for different drug modalities. And as you see here, we are developing antibodies, siRNA and enzyme which are enabled by our [ blood and brain ] technology. And the integration of the blood and brain technology and our sort of insightful drug, we think will lead to really novel breakthrough in neuro-degeneration.

I have a brief introduction by everybody in terms of backgrounds and so forth. Arnon, I want you start, then we can go to Giacomo.

Yes. So again, I'm Arnon Rosenthal. I'm the CEO and Co-Founder, was at Genentech for 16 years, then founded Rinat Neuroscience that developed AJOVY, the migraine drug that is now marketed by Teva, then co-founded together with Ben Barres, Annexon Therapeutics that's now is in Phase III with complement therapeutics for Guillain-Barre syndrome and geographic atrophy. And for the last 10, 12 years, Alector is my life.

Hello. I'm Giacomo Salvadore. I'm the Chief Medical Officer at Alector. I've been with the company for over 3 years. I've been in pharma for more than 15 years between Johnson & Johnson and Acadia and then Alector more recently. Prior to that, I was at the NIMH for 5 years, and I'm a psychiatrist by training.

I'm Eric Brown. I've been at Alector for 9.5 years now. And really the bulk of my time here has been spent the last 7 or 8 years building up the ABC platform.

And Neil Berkley, as mentioned, CFO and Chief Business Officer, been doing corporate development, business development, strategic financing, strategic marketing and things for about 25 years. Been started my career in very small companies, a couple of companies I helped found and ultimately exited and worked in companies such as GSK and other large companies as well. So kind of a broad breadth of experience across small and large pharma.

All right. Thanks for that. Arnon, you've been around for a while in neuro. Eric, you just mentioned 9.5 years at Alector. So you've also been involved in drug development for neurological indications for years. How do you think about the blood-brain barrier and its role in CNS drug development? How has this barrier historically limited the development of therapies for neurological diseases?

So the blood-brain barrier largely prevents the entry of large molecules to the brain. So if you look at antibodies, only 0.1% of the peripherally delivered antibodies can enter the brain. If you look at nucleic acid therapeutics or enzymes which have shorter half-life than antibodies, they do not enter the brain at all if you inject the delivery.

So the blood-brain barrier was a significant impediment to drug development in neurodegeneration and neurology in general. And I think once we are able, as you mentioned earlier on, once we are able to overcome the blood-brain barrier, we will be able to significantly expand the type of drug modalities that we can use to include nucleic acid therapeutics, enzyme replacement therapy for multiple lysosomal disorders that affect the brain and even antibody therapeutics that without the blood-brain barrier technology enter very poorly to the brain and do not distribute well to deep brain regions.

So I think that the blood-brain barrier technology could and would revolutionize sort of therapeutics for brain disorders.

Yes. Can you just briefly walk us through the mechanisms, the brain actually uses to transport molecules across the blood-brain barrier?

Sure. I mean this slide highlights it quite well. There is a variety of passive diffusion mechanisms, but those are only available for gases and very small molecules. Then there are solute carriers that move things like sugars and amino acids. And these are proteins that are on both sides of the barrier that facilitate passive diffusion.

And then you have the type that we utilize for blood-brain barrier transport, which is receptor-mediated transcytosis, which transports larger cargoes such as the iron carrying protein transferrin. And in this case, a receptor at the surface of the blood-brain barrier actually picks up a cargo on the blood side, translocates it physically through the barrier and then releases it on the other side.

All right. Eric, you spent many years working on antibody discovery and protein engineering to basically enable biologics across the blood-brain barrier. And Arnon, you also had a major role in thinking about the ABC platform, Alector's platform for crossing the barrier.

Can you just give us a quick overview, and we're going to get into detail shortly of how you and others are sort of exploiting receptor-mediated transcytosis to enable efficient delivery of these large drugs into the CNS?

Yes. Really, the key innovation here is to take the blood-brain barrier itself, the endothelial cells and turn them from a barrier into a highway into the brain. And the way we do this safely is not by just breaking the barrier open and allowing nonspecific transfer, but by utilizing these natural and very specific transfer mechanisms such as through the transferrin receptor mentioned above.

And this allows us because the brain is so highly vascularized, if you can actually translocate through the capillary network, then you're now able to deliver to every part of the brain, even the deeper brain regions that are minimally accessible to other types of brain delivery such as IT.

So what specific elements and sort of behavior of this crossing technology that we've seen to date sort of enable improved brain distribution versus conventional antibodies?

Yes. I mean I think the biggest part is really getting that broad bio-distribution. And again, so this relies on identifying a receptor that's not just highly expressed on brain endothelial cells, but on the capillaries itself. The capillaries are the smallest type of blood vessels in the brain that really vascularize the entire neuronal network. So it's basically said that like every neuron in the brain is fed by its own capillary.

So if you can enable transport through these specific cells and you're really delivering drug directly to the target cells throughout the brain. And what you can do with this is you can take a drug and the canonical example of this would be gantenerumab, right, which was ineffective without a blood-brain barrier technology attached to it, put the blood-brain barrier technology onto it. And suddenly, you have trontinemab, which is a very effective seeming drug in the clinic.

All right. So historically, neuroscience drug failures have been attributed to both target and biology limitations and challenges with CNS delivery. So how do you view sort of that balance between those 2 factors? And do you see new delivery technologies meaningfully shifting sort of the odds of success sort of going forward?

So traditionally, delivering antibodies to the brain has always been a challenge with less than 0.1% entering in the CNS. And the use of blood-brain barrier shuttles can help us testing validated targets and enhancing delivery in a different way and increase the probability of success.

Eric just mentioned the example of gantenerumab and trontineumab. Gantenerumab, it's a drug that showed 55- to 65-centiloid reduction measured with amyloid PET. And with the use of blood -- brain shuttle, trontineumab was able to induce a reduction of 84- to 99-centiloids as early as day 78 to day 196, while the gantenerumab studies were fairly wrong. They were 2 years duration.

What's even more striking is the percentage of subjects who become amyloid negative after treatment because gantenerumab was -- with 25%, 30% of the patients becoming amyloid negative. Trontinemab, which is gantenerumab with a brain shuttle, it may increase this number to 91% in 6 months. So this is a perfect example about how the use of brain shuttle can turn the fate of a drug that has failed earlier because of poor brain penetration.

So antibodies still work somewhat without the blood and brain technology, although as Giacomo mentioned, they do it poorly, but other types of drug modalities like lysosomal enzymes do not enter the brain at all if you inject them peripherally. Nucleic acid does not enter -- do not enter the brain at all if you inject it peripherally. So in these cases, [ blood and brain ] technology clearly transform the therapeutic potential.

And if you inject either enzymes or nucleic acid to the brain directly, it's a medical procedure. The drug do not distribute to the brain evenly. So in the case of drug modalities beside antibodies, the blood-brain barrier technology is clearly the main solution to the drug and the potential of therapeutics.

All right. So we see an approval here in the U.S., one in Japan for the -- for a drug that has this technology. But what do you see overall as sort of the next main target, which we can all guess what it is, but what is also sort of the low-hanging fruit?

Yes. So the low-hanging fruit, I think, are, again, anti-A-beta therapeutics that show some efficacy without blood-brain barrier technology, but significantly more sort of more rapid and more profound benefit with the blood-brain barrier technology and importantly, elimination of the main adverse effects of anti-A-beta therapeutics, the ARIA that's associated with blood-brain barrier technology.

So I think the lowest hanging fruit is anti-A-beta antibodies, and there is multiple companies are developing anti-A-beta therapeutics with blood-brain barrier technologies. I think the second low-hanging fruit are siRNA against the hallmark misfolded proteins of neurodegenerations like tau and alpha-synuclein. Both of these proteins, the pathology is intracellular.

So antibodies may not be as effective and the better way to counteract these misfolded proteins is with siRNA -- and again, if you can peripherally deliver nucleic acid therapeutics and the nucleic acid therapy will reach the brain. It's a lot more convenient that the drug distribution is much better with peripheral delivery. It's scalable. It's much safer. So I think that going after misfolded -- intracellular misfolded proteins would be the second sort of lowest hanging fruit.

And then lysosomal enzymes, there are over 50 lysosomal enzyme diseases. Many of them affected the brain. For example, GCase is one of the major risk genes for Parkinson's disease and Lewy body dementia, it's a lysosomal enzyme that -- whose loss of function leads to, again, lysosomal pathology and the disease. And until now, it was not possible to develop enzyme replacement therapy for lysosomal enzymes that affect the brain. And now with this brain shuttle, we are able to do this.

Right. So there are a number of active transport technologies that are emerging to shuttle these biologics across the blood-brain barrier. What are the key design principles that you believe will sort of determine whether these platforms succeed?

So I think there are several key principles that we look at. I mean, as we discussed, having the right receptor that has a strong expression on brain capillaries is important to get that widespread biodistribution.

And then optimizing the affinity, which is the binding strength of your binding domain to -- the receptor is very important and not just the affinity, but actually the kinetics we found optimizing how fast it binds on and off because really, this is an event where you need to bind on at one site on the blood-brain barrier and then be able to release on the other end to get it into the brain parenchyma.

And importantly, what we've noticed with our studies across multiple different cargoes is the optimal affinity you need differs quite significantly between different types of cargoes. But to your question about how translatable the platform can be within certain classes of molecules and especially classes that are chemically similar to each other, such as siRNAs, we have found that it is starting to be more and more plug and play where if you have a carrier that's really optimized for one type of cargo like an siRNA, it translates very well to another siRNA.

Okay. But overall, when you think about from antibody to siRNA or to enzyme, is it still sort of a plug and play or...

It's less plug and play. The enzymes in the siRNA have an important second mechanism where the carrier has to get it across the blood-brain barrier, but then it is also responsible for driving intracellular localization into a cell type in the brain such as neurons. And so this often means you need like a somewhat higher affinity.

You still need a balance, right? It still needs to be able to go across the blood-brain barrier and release, but then it also needs to drive entry into the neuronal cells and into specifically the endolysosomal system. So there's definitely a different optimal affinity and optimal format and characteristics needed for these different types of cargoes.

All right. I mean though you just sort of did touch on affinity, but how should we be thinking about the relationship between the receptor binding affinity and valency at the blood-brain barrier and sort of the efficacy of transcytosis into the brain?

Yes. I mean there's been a lot of studies on this, identifying that there's sort of an optimal maybe moderate affinity range where if you have too low affinity, you're not getting enough engagement at the barrier, you're not getting enough transport. If you have too high of an affinity, it's not coming off. It's doing things like driving receptor degradation.

And since you mentioned valency, often bivalent binders also tend to drive this degradative phenotype, which is a major safety risk in and of itself. I think the key thing that we've identified as we've undergone moving multiple studies from rodent models into the non-human primate system is that this optimal affinity window exists in most systems, but it's different.

And that's where there's been a lot of, I think, translatability gaps in our internal programs and within the field in sort of having to refine-tune the affinity as you move into non-human primates, which is why we really think it's very important to focus on non-human primate data to sort of validate that your platform works.

So the technology is largely plug and play, but you need to have a toolbox like a range of transferrin affinity that you can optimize for the drug modality for the requirement of whether you want an active or an inactive effector function for the half-life of the drug. So it's plug and play, but you still want to have a toolbox to really optimize the shuttle technology to the drug modality and the specific requirement of the target.

Do you think different receptors have different sort of optimal affinity windows based on their sort of intracellular trafficking?

For sure. I mean the affinity window is definitely going to be based on how fast the carrier itself translates through the blood-brain barrier and sort of the requirement for the antibody to be able to stay bound for that amount of time. Definitely, yes.

So Arnon, you just said that non-human primate data are important. How well does sort of the affinity exposure relationship observed in rodents model sort of translate to non-human primates and then ultimately to humans?

I mean I would definitely have to say not well between rodents and non-human primates. Like without getting too much into detail, we've taken multiple molecules forward that worked perfectly well in rodents, moved them into non-human primates and the performance was substantially worse in terms of brain uptake. And this is where really we've had to do like 7, 8 different NHP studies across different cargoes to now be at the point where we have molecules that are more or less plug and play for these different modalities.

So in other words, it's not so straightforward to develop this technology.

So rodents are not predictive at all for non-human primate and for human, like rodents have leaky blood-brain barrier, a very broad range of transferring affinity works really well in rodents. There is no difference in the -- brain entry between different affinities in rodents. And it's very different. The picture is very different than non-human primates, and we do think that non-human primate is predictive for humans.

So you can't really say anything about your technology before you really validated in non-human primate in the relevant dose. I think the relevant dose is also important.

A lot of publications and reports are, for example, these antibodies are at very high doses of 10 mg, 30 mg, 50 mg per kg, which significantly mask and nullify the blood-brain barrier technology effect. You really need to go to low doses like 1 mg to 3 mg per kg to start seeing the benefit of the blood-brain barrier technology and the differentiation between technologies.

Okay. Is there sort of a need for different PK profiles for different targets, meaning drug targets? And how do you think about that?

Yes. I mean I think the need for PK -- it's all dependent on the mechanism of action of the molecule, right? And the characteristics of the cargo. So if you have a cargo like an enzyme or an siRNA that will itself rapidly clear within the periphery, then you don't need a long-lasting blood-brain barrier technology. You need something that drives really fast uptake.

If you have, say, a blocking antibody, something that relies on the trial concentration, you need that to get into the brain, then you would want to pair it potentially with a blood-brain barrier technology that lasts longer in the periphery, maybe you pair it with half-life extension technology, a lower affinity binder. But again, it's all based on sort of the mechanism of action of your cargo.

And also the safety of your cargo like that means we didn't discuss it yet. But as you know, one of the on-target risks of the transferring based blood-brain barrier technology is anemia because there are 10x more transfer receptors on reticulocytes than on the blood-brain barrier. So a lot of your drug goes to reticulocytes. And if your drug is, for example, an effector function that can recruit immune cells, you basically bring activated immune cells to reticulocytes and that's what damaged the reticulocytes and leads to anemia.

So you can deal with it with either low affinity or as we dealt with it with identifying an epitope that reduce the ability to co-bind the immune cells and reticulocytes. But the safety is also a factor for the PK.

Okay. We will get into safety shortly with your molecule specifically, but so next slide, please. How do you think about sort of the selection of isotype backbone and Fc function? Is it something that can also be 100% modular and sort of plug and play?

So again, as Arnon just introduced, the safety really plays a role in how you think about what Fc component to use. So if you have a cargo like an siRNA where there's no need for effector function to drive the mechanism of the cargo, then you can go with a plug-and-play silenced Fc, and it really is, again, more on the plug-and-play side. But if you have a cargo like anti-A-beta where to drive phagocytosis of the target in the brain, you really need the ability of the Fc to engage those Fc receptors then it's a little bit less plug and play, right?

So then in that case, you want to utilize that full effector function molecule, and we have to modulate the affinity and especially we get into a lot of the epitope of TfR that we're binding in order to still drive strong brain uptake but to get safety with using that fully active Fc.

All right. So what are actually some of the nuanced details and sort of mechanisms that may lead to an optimal or more optimal from a safety perspective and efficacy profile?

Yes. I mean, definitely, selecting on the epitope and the binding kinetics are 2 of the most important ones. If you're talking about a transferrin receptor binding blood-brain barrier transfer technology specifically.

So in our case, we sort of engineered a unique epitope on the transferrin receptor that still doesn't interfere with the native function, still drives best-in-class brain uptake, but also sort of decouples a little bit the ability to co-bind the transferrin receptor and then still have the Fc engage innate immune cells such as like natural killer cells in the periphery, which drive some of those hematological safety risks that Arnon already introduced.

Different companies are dealing with the safety efficacy profile differently and especially it comes across with the anti-A-beta antibody. So some companies completely use an inert effector function. Basically, they engineer the constant region to not to be able to bind immune cells to the Fc gamma receptors at all, and they rely on other like what's called nonclassical phagocytosis mechanisms to remove A-beta.

Other companies cripple the effector function and try to thread the needle between safety and efficacy and basically partially mutagenizing the constant region in different ways.

And again, we found a different solution. We think that a full effector function is essential for full efficacy and that you can't really modulate the effector function without impacting efficacy and you need to find another solution. And again, our solution was to find a different epitope that can disconnect anemia from removal of A-beta plaques.

Is there a possibility -- and I would assume the sort of modality specific as well as target of marrying this tech with an extended half-life to further decrease dosing?

It's certainly possible, but it really is based on the properties of the cargo. If your cargo itself is driving strong target-mediated clearance, then half-life extension technology isn't really going to give you much of an effect. So this is obviously the case with these enzyme and siRNA cargoes. It's possible for like an antibody cargo that has low target-mediated clearance in the periphery.

But again, if you're using like a high affinity TfR to drive really strong brain uptake in a short period of time, you're still, again, not really going to be able to rescue that with half-life extension technology, because half-life extension technology only really rescues you from like the native background level of clearance that happens, not from specific target-mediated clearance.

So again, the transferring is a very potent target-mediated clearance. So half-life extension could have limited impact. And also specifically for anti-A-beta antibodies, the half-life extension could have both cons and pros like the cons are that if the antibody is present longer in the periphery, it has a higher possibility of interacting with reticulocytes and leading to anemia.

It has higher possibilities of interacting with vasculature A beta plaques and leading to ARIA. So you really, again, have to weigh the cons and pros of longer half of half-life extension, which is dependent on the target.

Okay. So what are the key biological properties that sort of make a receptor well suited for ferrying cargo across the blood-brain barrier? And do you see the field sort of converging around a few optimal receptors? Or will different receptors be sort of required for depending -- depending on the cargo type or therapeutic type and indication?

Yes. I think one of the key properties, obviously, is that high expression on the brain endothelial cells. Ideally, you want to have very specific expression, so high expression in the brain and low expression in peripheral tissues. Obviously, it needs to be able to drive strong transcytosis.

And I think one of the most important ones is that it actually has minimal or manageable target-based adverse effects. And this is where transferrin receptor does have a known class effect with these hematological side effects. But again, it's known, it's monitorable, it's manageable. Any new target introduces a whole new suite of potential safety risk that needs to be mapped out and derisked both in non-human primates and in the clinic.

And that's why we think for the next -- both short and probably medium term, transferrin receptor is the most validated and the field is converging around transferrin receptor, and it will dominate the field again, in the next probably 3 to 5 years because of that clinical validation.

Proof of concept for these new targets is, I would say, years away, especially for the ability to really utilize them more broadly. Again, when we're talking about these internal cellular targets, things like siRNA and enzymes, the transferrin receptor has a very favorable dual mechanism where it both is able to drive entry into the brain, but also drive entry into cells in the brain.

And we've shown this now for neurons, astrocytes, microglia. So all the key cell types in the brain are actually able to deliver intracellularly after you cross the blood-brain barrier. And this is something that I don't think has been mapped out nearly as well for any of these other receptors.

So the transferrin receptor is responsible for that, isn't?

Yes.

I guess what sort of drives into my next question is what biological properties make it particularly well suited for receptor mediated transcytosis?

Yes, exactly. That ability to drive strong uptake across the blood-brain barrier, strong uptake in the cells. The transferrin receptor drives entry through the endolysosomal system. So again, if you're delivering a lysosomal enzyme, that's perfect because you're getting into that system.

The same thing for siRNAs, therapeutic siRNAs need to be delivered into the endolysosomal compartment at the end of the day for the antibody part to be degraded off and the siRNA to undergo endosomal escape and get into the cytoplasm where it ultimately has its effect. So that is a very favorable property of transferrin receptor.

So how does the sort of receptor-mediated uptake between transferrin receptor differ from the other sort of transferrin receptors, which is currently being evaluated IGF-1R or CD98 heavy chain? And in terms of intracellular trafficking and sort of distribution into the brain.

IGF-1R has a different non-endolysosomal mechanism for uptake. There is a nice publication recently that highlights the mechanism. So that can be favorable for delivery under the parenchyma, although anti-IGF-1R has never shown as high of absolute brain uptake as a TfR-based shuttle.

And then CD98 has a much different kinetics of uptake, which can make it favorable in some applications. But again, that one has not really undergone the validation in non-human primates and in the clinic to show that it can both be translatable and safe for delivery.

So there are multiple groups engineering these blood-brain barrier penetrant therapeutics. Sort of what metrics should investors focus on when sort of comparing the different platforms?

Yes. So basically, the parameter should be like the fold penetrant into the brain and like this should be measured by absolute concentrations of the drug in the brain, not by relative concentration. Again, a lot of the publications are looking at relative like fold elevation in the brain compared to the periphery and compared to naked drug.

If your naked drug is degrading quickly or is a lousy drug that doesn't enter the brain, the fold elevation could be misleading. So you want to show with absolute concentration of drug that you have like meaningful elevation of drug in the brain. It has to happen at a low concentration like that enable like subcutaneous delivery that basically enable the advantage of blood and barrier technology to reduce the drug dose for both safety and convenience of use.

So you want to see high brain penetration at low drug peripheral dosing. You want to see manageable safety at least, again, starting in non-human primates, not just in rodents. You want to see that the shuttle does not impact the normal function of the receptor like in the transferring receptor case, for example, you don't want to disrupt iron transfer to the brain or iron transfer to reticulocytes. In CD98, you don't want amino acid transport to be impaired.

So you want -- again, basically, you want to see good safety or manageable safety, good brain delivery at low dose and durability that basically you don't down-regulate the receptor, you don't degrade the receptor, you don't saturate the receptor very quickly. So you want to see -- and you want to see also the drug configuration that you have is commercially or clinically viable that you can manufacture it at high level, that you can store it, that you can basically give it to human.

Okay. So next slide, just can you sort of give us a high-level overview of the ABC platform in terms of target selection, modalities, even though you did touch on it, that can be leveraged. And just what gives you confidence at a high level that you have candidates derived from the ABC platform that are sort of ready to enter the clinic?

Yes. So Eric, I don't know if you want to answer that. But yes, as Eric mentioned, we tested our blood and ABC technology in multiple like in over 8 non-human primate studies with 3 different drug modalities, enzymes, nucleic acid and antibodies. The shuttle configuration, the blood-brain barrier that transferring valency, that transferring affinity, that transferring binding kinetics are really tailored for each drug modality.

The constant region of the antibody is tailored for each drug modality, the location of the blood-brain barrier, the transferring binding epitope is tailored to each drug modality. So we really engineered our blood-brain barrier shuttle for siRNA specifically, for antibody specifically and for enzymes specifically to really optimize all the aspects of the combined drug.

And as a result, in non-human primate, we do see very sort of durable and broad brain distribution with low dose delivery and we see drug efficacy. We see with siRNA, for example, we see profound reduction of the target siRNA, for example, tau. With enzyme replacement therapy, we see significant elevation of the enzyme in multiple brain tissues with enzyme -- with antibodies, for example, anti-A-beta, we see 4- to 12-fold higher brain concentrations compared to competitors.

So basically, we have multiple validating data in -- primarily in non-human primates with multiple experiments with different dosing regimens, different drug modalities, different durability that really validate our platform.

The key thing I would add there, just to this not being a simple endeavor, we didn't get clinical candidates out of our first NHP study or our second NHP study or our third NHP study. We got clinical candidates out of our sixth NHP study, our seventh NHP study and our eighth NHP study.

And that's sort of the depth of knowledge it took to get to the point where we didn't just have drugs that are good enough, but like really have the potential to be best-in-class. And again, it really relied on that validation in the NHP system, not in anything we were seeing in murine models.

All right. We're going to get into details shortly, but just from a high level, again, what is differentiated about your platform versus other transferrin-based approaches?

Again, just the breadth of tailored shuttles that pair with each of these different modalities. the different kinetics we can access, the different Fcs, the different formats that we use. On A-beta side, sort of that novel epitope that we'll talk about in more detail later, that allows us to utilize the full effector function and still have a manageable safety profile. And then at the end of the day, the validation in all of those different NHP studies covering all those different modalities.

Okay. And when you say a novel epitope, you mean epitope on the carrier...

Carrier -- on the transferrin receptor.

Okay. From an engineering perspective, how is transferrin binding sort of incorporated into the ABC platform? Is it binding via a Fab fragment engineered into the Fc domain? Or is it ScFv, VHH or peptide? Will it be a combination of all or just sort of multiple interchangeable modules?

So we utilize multiple types of modules. The key design philosophy is to minimize interference with the function of the cargo. So in the terms of an antibody, we're appending something like an ScFv on the end of the Fc as far away from the active fab end of the antibody as possible.

And then with enzyme and nucleic acid cargoes, we can utilize an anti-Fab or a Fab anti-TfR binder paired in different ways. And again, it all -- you have to test like multiple combinations to figure out how the molecule goes together in a way that both works therapeutically, but is also like highly manufacturable and stable.

We did try utilizing engineering binding into the stock domain itself, and we found that it was really significantly different to engineer the breadth of affinities and epitopes that we wanted. And so we kind of actually gave up on that approach and stuck more to the antibody fragment-based approach.

Okay. We did touch on it a little bit before, but again, what are sort of the key trade-offs between monovalent and bivalent transferrin receptor engagement? And what factors, whether it be the cargo, modality, safety or something else drive the decision on which sort of format to choose?

Yes. I would say for brain delivery monovalent formats are strongly preferred. Bivalent formats really have a very strong potential to drive receptor degradation by cross-linking receptors and driving them directly into the lysosome.

So unless you're a company like Avidity where you're actually trying to deliver into target cells in the periphery, we would encourage the use of monovalent because you really need that antibody to be able to bind to the target and then come off at some point. And bivalency really drives towards binding and then staying on or even cross-linking the receptor.

Awesome. Yes, a bivalent invariably increase the binding stress, the receptor to a point where, yes, it's hard to dislodge the shuttle from the receptor and this irreversible or almost irreversible binding leads to receptor internalization, transferring receptor degradation and in some cases, would lead to either anemia, is another way to lead to anemia if you degrade the transferring receptor.

And if you degrade the transferrin receptor on the blood-brain barrier, you cannot really transport drugs through the blood-brain barrier. So bivalency is really primarily effective when you want to transport drugs to the muscles where receptor degradation doesn't really matter.

All right. A little bit more details about your candidates. So you show a very wide range of transferrin receptor binding affinities. How do you select these binders? And do they provide a sort of an affinity response curve? And although we touched on it before, sort of a broad question for the ABC platform, how do you think about optimal affinity window for brain delivery?

Yes. I think the interesting thing here is you see binders across a 1,000-fold range of affinities. All of these binders worked in the murine system to drive very strong brain uptake and actually not that much but surprisingly consistent brain uptake between even single-digit nanomolar and single-digit micromolar binders.

It was really when we moved in the non-human primates on the right side of the slide, you can see 3 binders that work equally well in the mouse have up to a fourfold difference in performance in the non-human primates. So we really had to sort of fine-tune that window in the non-human primate system to really give us the best sense of what the optimal affinity window is.

And then again, it is, again, different when you move from an antibody cargo to something like an siRNA, where, as I said, you have that dual mechanism where it needs to translocate into the brain, but also drive uptake in the cells. So that itself requires a different affinity window.

All right. Can you just actually walk us through the middle figure, sort of what does the experiment sort of tell you about affinity and receptor binding and internalization and how this sort of will translate to in vivo brain exposure?

Yes. In a broad sense, the middle figure here is showing the first step of the transcytosis process, which is the ability to engage the receptor on the surface of brain endothelial cells. And that process tracks very well with affinity. So a higher affinity binder will drive stronger uptake into the cell. So basically will drive the first step of the transcytosis mechanism. But you really have to go in vivo to elucidate the entire mechanism where it actually has to translocate and then fall off and translocate into the parenchyma.

Okay. How many modalities sort of have you tested with the -- in either mice or non-human primates? And do these -- do you see modality-specific optimal affinity ranges, which I assume you sort of touched on before, so I assume yes. For example, siRNA conjugates sort of require different affinity windows versus antibodies and enzymes?

Yes. So we've tested actually 13 different cargoes in the murine and non-human primate system, including the 8 non-human primate studies I mentioned before. And I think we really are seeing that for certain cargoes like the siRNA, there is really an optimal affinity or even just an optimal binder and format that you can make much more plug and play and you can just take a new siRNA and put it on the same binder and get a very similar performance.

So it's really -- you have to test it experimentally. Affinities that work well for antibodies don't work at all for siRNA or for enzymes. You really have to test each drug modality and identify what's the optimal bell curve for a given drug modality and drug configuration.

And again, the reason is that antibodies have significantly longer half-life in the cell. You can get away with lower affinity. There is more time for the drug to enter the brain. siRNA and enzymes have short half-life in the cell. You have to really push them through the blood and barrier much more rapidly and then you need much higher affinity. So the affinity ranges of antibodies, enzymes and siRNA are very different like the optimal affinity is.

All right. Next slide. Can you just sort of walk us through what is structurally distinct about your ABC transferrin receptor, I guess, binder versus other platforms? And does the epitope matter?

Yes. So we identified an epitope that is on, I'd say, the side of the transferrin receptor molecule. So it's still far enough away from the binding side of the native ligands like transferrin or ferritin, so it doesn't interfere with their binding, but it's not located on what we call the tip region of the apical domain, which is where some of our early antibodies and some of the competitor antibodies such as Roche and Denali bind.

And we find that binding this epitope allows us to partially decouple antibody effector functions such as ADCC, which is the innate immune system-mediated mechanism that drives the hematological toxicity. We can sort of uncouple that from the affinity of the TfR and enable us to utilize higher affinity TfRs to drive stronger and faster brain uptake while still minimizing the possibility of use of downstream effector functions such as ADCC.

So I'm just going to make a comment here because people look at this and if you're not a structural biologist, you probably have no idea what you're really looking at. And so I guess the green domains are the ligand for the receptor, correct?

The light green and the yellow domains are the ligand itself bound to the receptor, so they're blocking sort of the region of the receptor that they bind to. And you want to make sure you're binding to a region that's not where that light green or the yellow domain is to avoid interfering with native function.

So the receptor is the dark and light blue, the transferring receptor and the transferring ligands are the green and the yellow. And you want to bind your shuttle, basically, you want again Trojan Horse that use the receptor, but don't disrupt its function. So you want to bind in a region that is away from the ligand binding domain. So there is really no physical interaction and no disruption of the physiological function of the transferring receptor.

How tightly coupled are our TfR affinity or epitope and ADCC risk, assuming that the Fc effector function is not silenced?

Yes. So that's a great question. Within an epitope, so within antibodies that are binding the same epitope, the ADCC window really correlates directly with affinity, right? So stronger affinity will give you higher ADCC at lower antibody concentrations. But what the figure on the right is showing is the ability to uncouple it by using a different epitope. So the blue and the green binders there are much higher affinity antibodies that bind to the ABC epitope.

And then the red is a much lower affinity antibody that binds to that more exposed epitope on the tip of the apical domain. And you can see even though the antibodies binding the ABC domain have much higher affinity, they drive a significantly lower ADCC response. So again, within an epitope, it is affinity driven, but you can break that relationship somewhat by utilizing a more optimized epitope.

All right. What are the safety -- I mean, we sort of touched on it again, so briefly in 1 minute or less, what are the safety considerations or theoretical safety concerns with chronic TFR engagement with repeat dosing. Next slide, there we go.

Yes. So one of the main concern is related to the anemia. We have to remember that anemia is very frequent in elderly subjects and even more so in patients with Alzheimer's disease who display a rate of baseline anemia that is between 20% and 30% and half of it is a moderate anemia degree.

And any drug that worsen baseline anemia that can make it symptomatic or more severe, I think it's going to be problematic, especially when the drug is administered outside the rigorous setting of a controlled clinical trial when it's administered to patients in the general population, I think it's going to be particularly challenging.

And now the drugs that are in development, they require careful monitoring of hemoglobin, red blood cells periodically and to look at particularly drop threshold compared to baseline or levels of hemoglobin. I think a drug that doesn't have these liabilities that can be administered safely in this vulnerable population with high rates of undiagnosed anemia will be really transformational.

Okay. Sort of skipping a little bit forward, we did touch -- Giacomo did touch a little bit on trontinemab. But from a safety perspective, there were a lot lower rates of ARIA for trontinemab versus other plaque reducers like lecanemab and donanemab. Why do you think this is the case? And will this actually translate broadly across all A-beta therapies that have this blood-brain barrier crossing that?

Yes. We believe that one of the reasons why underlying the lower ARIA rate observed with trontinemab is the fact that there is not much time when the drug is actually present in the large blood vessels, therefore, allowing the drug to bind to the amyloid that is present in the large blood vessels and then therefore, damaging and causing edema, ARIA-E or hemorrhages. So I think this is going to be a broad characteristic of drugs which have the blood-brain barrier technology.

And it's important to note that there is a background ARIA rate in Alzheimer's disease that is typically less than 5%. So the absence of ARIA, I don't think it's an attainable goal, but what will be important to show no increase over background ARIA rate in patients with Alzheimer's disease, therefore, waiving the need for repeated MRI assessments as part of the safety monitoring.

Approved anti-amyloid treatments require 5 serial MRIs with a different time, especially at the beginning of treatment and then more MRIs if needed in case subjects become symptomatic and there is suspicion of them having developed ARIA.

So -- and this comes with significant challenges for patients as well as the healthcare system. So I think that's another big advantage of drugs, anti-amyloid treatments that are paired with brain shuttles in terms of their ability actually to be prescribed more broadly to the patients with Alzheimer's disease.

All right. Moving specifically to your candidates, AL137 or 037, specifically against PyroGlu3 A-beta, similar to donanemab, how much derisked the target to a degree. What's your sort of rationale for choosing that target versus other A-beta species?

So I think that donanemab data with all the shortcomings that we discussed in terms of safety, et cetera, they show very strong amyloid clearance, much stronger than lecanemab. The number of amyloid negative subjects at the end of the Phase III trials is double for donanemab versus lecanemab.

And donanemab is a PyroGlu3 antibody, which is species that is present in the plaques. And so therefore, even the greater clinical efficacy and greater amyloid reduction of drugs with -- that target this PyroGlu3 epitope, I think it makes perfect sense once we decide to develop an amyloid antibody with the brain channel to choose this kind of target.

Do you believe full effector function is actually required for meaningful plaque clearance once you achieve higher brain exposure? And the reason why we ask is because there are a couple of candidates out there that don't have effective function at all.

Yes, we do think that it's critical. Basically, all the antibodies that have shown efficacy in the clinic, donanemab, lecanemab, aducanumab has full effect of function. Antibodies with not a full effect of function like ranibizumab did not show efficacy, was an IgG4. So we do think that very aggressive removal of A-beta plaque is essential.

Also, you have to know that, yes, we talked about gantenerumab. Gantenerumab was able to reduce A-beta plaque by 60%, 70%, and it didn't lead to clinical benefit. You need to extensively remove A-beta plaques beyond 70%, closer to 80%, 90%, 100% to get clinical benefit. And if you cripple your effector function, your likelihood in our view of being able to do this is significantly reduced.

So we think that every drug that modulates, that cripples the effector function to achieve safety against anemia is going to pay with efficacy. And again, time will tell, but that's really what the data tells us so far.

Okay. Moving on to the next slide. What are sort of the exact differences between 037 and 137? And how should we think about functional differences between the 2 molecules?

Yes. Really, the only functional difference is the strength of the binding to the transferrin receptor. So they utilize the same anti-beta domain, the same Fc, but they utilize 2 different anti-transferrin binders that have about a 15-fold difference in affinity. And as you can see on the serum PK curve, 037 -- sorry, 137 utilizes a higher affinity anti-TfR and that drives stronger brain uptake at the shorter time period, but also drives faster clearance.

And then AL037 has a weaker affinity TfR binder. So you see that the peripheral clearance is much more similar to a naked antibody, but you have a little bit lower brain uptake at the initial time point, which will probably translate to higher brain uptake at later time points because you have more retained in the serum.

And then there's also different potential for safety with the 2 different TfR affinity. So that's something we're extensively mapping out. We're doing GLP studies on both of these molecules to determine which one has the best balance between efficacy uptake and safety.

So you have faster clearance with 137, but I'm assuming this is measurement of serum. And so that's likely going into the brain because you can see to the right-hand side, you have higher exposure levels...

Exactly. So with the higher affinity, you're driving higher uptake into the brain and also into TfR expressing tissues in the periphery. So that leads to a faster decline in the serum. But again, if the trade-off is getting the drug to where you want it to go, then that can be a trade-off worth taking.

Okay. And are you able to make any type of sort of comparisons to exposure levels for trontinemab -- to trontinemab?

Yes. I mean we mapped this out for both of these molecules. So actually, in their published NHP data at 10 mg per kg dosing, we still see higher -- significantly higher brain uptake for both these molecules at a significantly lower dose of 3 mg per kg. And we calculate that if you normalize it out, we're seeing a 5 to 10-fold increase in brain exposure in the brain itself, in the parenchyma over trontinemab if you sort of normalize for the equivalent dose.

Okay. So next slide, how can sort of a short systemic half-life for 037 or 137 than a naked antibody sort of help improve safety?

So there's 2 points. As Giacomo mentioned, the ARIA risk is really driven by exposure of the antibody to those central amyloid deposits in the larger blood vessels. So if you can decrease both the dose you need and then the clearance, that will reduce the amount of time that large levels of antibody are present in those large vessels to interact with the central amyloid deposits and drive ARIA.

And then hematological tox is similar. It's reliant on the presence of a large concentration of antibody within the blood vessels to interact with the reticulocytes and actually drive that damage. So as soon as the antibody concentration, the serum drops below the level where you're inducing that damage, then the system can begin recovery. So if the antibody clears faster, you reach that recovery phase more quickly.

Awesome. Is there anything else you want to sort of disclose about this program specifically before we just briefly ask you about your 2 other programs?

Yes, again, that's sort of -- we think that we have a really good combination of efficacy and safety with this antibody. We are not sacrificing one for the other. So we think that overall, we could really have a very potent and safe drug and that would be very competitive. And our goal is to deliver it subcutaneously. Based on our modeling, we think that 1 mg to 3 mg per kg once a month, even with subcutaneous delivery will be more than sufficient to lead to complete removal of A-beta plaques.

So we have a drug which we think, again, it's very potent because it has a full effector function, has manageable reticulocyte effect because of the unique epitope and enters the brain to very high concentrations and could be very competitive in the field.

Very awesome. So just briefly touch on your other disclosed programs or at least 2 of them, siRNA, Tau program. I know you've generated a lot of preclinical data, but just can you provide a brief overview of this program and sort of key data you would like to highlight?

Eric, do you want to address that?

Yes. I mean I think one of the key things and even just showing on this slide is that with our delivery platform, we're seeing very consistent delivery across different brain regions. And this is stand and start contrast to things like IT injection where you can see up to a 30-fold difference in the actual siRNA concentration between different brain regions, we're seeing at most like a threefold difference.

And at the same time, we're seeing both very high absolute level of siRNA accumulation. So in this case, well over 100 nanomolar accumulation of the siRNA cargo, and that leads to significant knockdown across all those multiple brain regions.

Did I hear you correctly, 30% variation when you have intrathecal versus 3% variation?

30-fold variation and 3-fold variation. So it is quite extensively -- because you're injecting into the spinal cord and you're relying on sort of a passive diffusion mechanism. So based on how close the brain region is to the injection site, you can get much more or much less of the drug.

Yes. And the reduction in sort of the knockdown of mRNA really translates to reduction in phospho-tau protein, both in brain tissue and in the CSF and it's durable like we measured in tissue up to 98 days after like 3 weekly injections, we see around 60% knockdown of the phospho-tau protein.

So we have a very sort of a durable effect. I mean we have an siRNA drug that can be injected peripherally, and we are going again for subcutaneous delivery that reach the brain, that distribute in the brain very broadly, that leads to significant knockdown of the target mRNA and resulting in significant and durable knockdown of the phospho-tau protein in brain tissues.

So we are, again, very excited about this program. We think it could go either as a stand-alone drug to enhance the efficacy in Alzheimer's disease or potentially could go sort of in combination with anti-A-beta therapeutics to really push again the clinical benefit that is limited in anti-A-beta antibodies on their own.

Okay. That is the future combinations. So next slide, I know you have generated again preclinical data, but can you just sort of provide an overview of the GCs program and sort of key data that you just would like to highlight?

So GCase is a lysosomal enzyme that's basically loss of function of this enzyme is associated with a significant percentage of Parkinson's disease and significant percentage of Lewy body dementia. And although the concept of enzyme replacement therapy is very validated in the periphery, like in Gaucher disease, for example.

It's -- until now, there was very little ability to elicit enzyme replacement therapy in the brain, like there is sort of a drug for Hunter disease that sort of, again, it's a lysosomal enzyme that affects brain that leads to brain pathology. But there is really -- until now, there's no ability -- there was no ability to deliver GCase enzyme to the brain for Parkinson's disease and Lewy body dementia.

And we were able to overcome 2 major issues with this approach. We were able to engineer GCase. The natural GCase is very -- has very short half-life and mediocre activity. We were able to engineer the enzyme itself to have up to 50-fold higher activity and stability, and we were able to enable delivery to the brain following peripheral injection with our [ blood and barrier ] technology.

So we see, again, with peripheral injection, we were able to show in non-human primate broad distribution in multiple brain tissues, including relevant brain tissues like the substantia nigra and the putamen that are affected in Parkinson's disease. We were able to show more than doubling of enzymatic activity. And in rodent disease models, we were able to show very durable effect, a single injection is effective in reducing the toxic substrates that is accumulated in the absence of the enzyme.

So we are able to reduce the toxic substrate for over a month with a single injection. So we think that we have a really exciting enzyme replacement therapy for Parkinson's disease and Lewy body dementia that are caused by GCase deficiency.

And we think that this therapy could ultimately also be beneficial for sporadic versions of the disorders because Parkinson's patients, for example, that have lower than normal level of GCase and higher than normal level of the toxic substrates progress significantly faster than other sporadic Parkinson's patients. So we think that, that could be the first and best-in-class GCase enzyme replacement therapy for -- again, for these 2 disorders.

All right. Thank you very much for that. And we are a little bit over, but not a big deal. Last 2 questions. Neil, if I've not heard from you, so let's hear something. How are you thinking about BD? Are you looking to sort of partner out specific candidates? Or if large pharma wants to license the platform for specific targets, are you open to that? Or will it be a combo of both?

Yes. Thank you very much. We're very -- we're focused on asset-focused deals. So we're primarily focused on discussing the potential of partnering around specific assets where we can capture our full value of those programs.

I mean as part of one of the relationships around an asset, we could consider broader platform access, but it would be in the context of an asset anchored deal. We're not and have historically not pursued stand-alone platform type just enablement of someone else to use our platform to develop their drugs. That is not something that we have pursued.

Okay. I'm going to ask you how active have you actually been on the BD side? And like the reason -- one of the key reasons why I'm asking is that when I was in San Fran in January, any company that had an asset that needed to go into the CNS, they were looking for some type of platform to link to.

And then companies like you that I met said you were quite busy with BD. And so just how busy have you been? And can we expect to hear some type of deal within the next 12 months or so?

We've been very engaged with pharma partners. Very strong engagement, very strong appreciation for what we're doing, very strong interest. And they know that we've been working on this for a long time. We've been working on this for 7 years. So there's a lot of knowledge and credibility behind our platform and what we're doing. So partners are very engaged.

We will -- we're being very selective about what we want to do. We're excited about our pipeline, and we're being selective about how we're going to partner those, and we're focusing on transactions that reflect the value and asset of those platforms -- of our platform and our assets. Can I do -- as a BD person, I formally don't make predictions on deals, but I do think the engagement could lead to something over the next -- definitely 6 to 12 months as you suggest.

All right. That's great to hear and excited to see what comes out. Last thing is next sort of key milestones for the platform over the next 12 to 24 months?

Arnon, do you want to take that?

Yes, sure. Yes. So we are advancing our anti-A-beta antibody. It's going to be in the clinic in the next sort of definitely less than 12 months. And we know now how to really look at efficacy in Alzheimer's patients with a small short clinical trial. We are going to sort of look at profound reduction in A-beta plaques with PET imaging. We are going to look at multiple biomarkers. We are going to look at minimal or no ARIA, sort of very manageable anemia risk.

And we are going to also look at minimal infusion reactions, which is one of the liabilities of some of the competing drugs. And we are going to, again, do all of this move very quickly to subcutaneous delivery for maximal convenience of use.

So the anti-A-beta drug is going to sort of have initial proof of concepts in the next 2 years. We are advancing our Tau siRNA to IND and into the clinic in the next 2 years and also possibly the alpha-synuclein and the GCase programs. So in the next 2 years, we'll have multiple sort of drugs going to IND and beyond.

Awesome. Thank you very much for that. Thank you very much for your time. Really appreciate it. I think a lot of insightful sort of nuance and information. So thank you, and also thank you to the audience for listening in.

Thank you very much for having us. We really appreciate it. Thank you.

All right. Good afternoon, everyone, and thank you once again for coming to the 46th Annual TD Cowen Healthcare Conference. I'm Steven Ionov on the biotech team, and I'm joined by the management of Alector Inc. We'll be hearing a presentation first from Eric Brown, the Head of Antibody Discovery and Protein Engineering, and then we may take some questions. So Eric, thank you for coming. Take it away.

So in addition to my role leading antibody discovery and protein engineering, I've also been heading up our ABC platform for the last 7 or so years, and that will be the primary focus of our talk today. So if you look at our -- if you look at our portfolio here at Alector, we do have one non-ABC-enabled program, AL101, which has an interim futility analysis in the first half of this year conducted by an independent monitoring committee.

I will not be talking about that particular program today because the focus is entirely on our ABC platform, but I will be talking about the rest of these programs, including our lead antibody candidate, an Aß antibody enabled by ABC, our lead enzyme candidate, which is a GCase enzyme. Both of these programs are headed towards IND.

And then I'll introduce our siRNA platform, which is also being enabled by the blood-brain barrier technology as exemplified by our TAU ABC molecule and then there are a couple of other lead molecules or follow-on molecules that I will identify in our siRNA platform.

So to get into our ABC technology, we started on this, as I said, about 7 years ago, casting a very wide net looking at a number of blood-brain barrier receptors, including transferrin receptor, CD98, IGF-1R. Through several years of work, we've sort of honed in on TfR as the one most ready for platform applications.

Even within TfR, there's a very wide range of potential ways to go. So we honed in on both the specific epitope on TfR and a very wide range of affinities to build a broad toolkit to apply across a wide range of cargoes. And then really, we spent the last several years on what actually turns out to be the trickiest part of this, which is applying the specific ABC of interest to the specific cargo, putting them together to make a molecule that both crosses the blood-brain barrier, is efficacious on the other side of the barrier. And then lastly, obviously, is a highly manufacturable and scalable therapeutic.

And in the course of this, we've actually taken -- it says 12, but it's actually 13 different cargoes that we've applied antibody electric brain carrier technology to. So this is a mix of antibodies, enzymes and siRNAs.

And in that case, we've actually taken all of these in vivo, many of these into NHPs, and we've finally gotten to the point, I think, where we really have excellent ABC technology to deliver all sorts of cargoes, antibodies, enzymes and siRNAs.

And as you'll see, there are slight subtle differences for each of them that we'll get into in each section. So one of the unique properties of our ABC platform versus other TfR-based platforms is the epitope that we're using.

So if you look on the left -- on the right side -- left side of the screen, you see a schematic of the transferrin receptor in blue. And then appended to that on -- in green and yellow is a schematic of the native ligand transferrin.

So initial efforts to utilize the transferrin receptor as a blood-brain barrier receptor focused on what I'm calling the elector epitope B, but you see it is also highlighted as where the Denali ATV epitope and the trontinemab epitope from Roche are. So this is at what we call the tip of the apical domain.

So this is an epitope on TfR that's very available for binding, does not interfere with binding to the native ligand. But the problem in a sense of this epitope is if you bind an antibody there, then the Fc of that antibody is very highly exposed in order to bind to innate immune cells, which is what causes the downstream safety functions such as reticulocyte depletion and anemia that are commonly seen with anti transferrin receptor antibodies, particularly those utilizing an active Fc.

And this is very important for our case because we are utilizing an anti-Aß antibody that we feel requires fully active Fc in order to have the highest possible Aß phagocytosis.

So in addition to looking at antibodies that well-characterized epitope B, we also search for an alternative epitope that would drive the strongest possible brain uptake but also ameliorate the safety liabilities. And we found what we call the ABC epitope here on the side of the transferrin receptor.

So antibodies are able to bind here. They don't interfere with transferrin binding. They don't interfere with the native function, but they do show very strong brain uptake. And now we've somewhat disconnected the ability to drive brain uptake with the ability to drive these downstream effector functions. And we can highlight that in a number of different ways.

If you look at the middle of this slide, you'll see an in vitro ADCC assay where we show an antibody in red against the exposed epitope B, where we can drive a strong productive ADCC response through the transferrin receptor versus antibodies in green and blue that bind at our ABC epitope.

And even though these are significantly stronger, higher affinity antibodies, they drive significantly less of an ADCC response. And then this translates in vivo on the right-hand side of the slide to decreased reticulocyte depletion in the murine system.

So in this case, we took 2 antibodies with the same affinity dosed at a relatively low therapeutic concentration of 3 mg per kg, and we see the antibody binding at epitope B in red shows very significant reticulocyte depletion, whereas the antibody binding our lead epitope in blue, the ABC epitope shows very minimal reticulocyte depletion.

We actually carried this forward into non-human primates to show that we see significant amelioration of the safety. So I'm going to show on the next 2 slides, 2 match studies where we did tox dose evaluation of an antibody that binds at the exposed epitope, which would be this slide, even with a partially active Fc.

This is the c-LALA-PS type of mutation. In this case, we see both reticulocyte damage, but more importantly, over time, you see in the middle and right side of the slide, sustained depletion in both red blood cells and hemoglobin, which is what leads to an active anemic phenotype.

On the next slide, we'll show a very similar study design also in the NHPs in this case, with a full effector function where we utilize our proprietary ABC epitope with a similar affinity binding to TfR. In this case, while we still see some transient decrease of reticulocytes, you'll see over the course of the study between each dosing interval, the reticulocytes have time to recover.

And thus, because they're recovering between each interval, you don't see any decrease in either red blood cell counts or hemoglobin over the course of the study. And again, this is a tox dosing study, so it's very high dose repeat. This is sort of the worst-case scenario for this particular antibody.

Getting back to the ABC platform as a whole, we've actually validated on the left side, binders to anti transferrin to transferrin receptor across a 1,000-fold range of affinities. All of the binders on the left side of the slide actually work to drive significant brain uptake in the murine system.

And what we've really noticed, I think one of our biggest learnings from 7 years of working on the system is how disconnected the murine and NHP results can be at times. So when we took antibodies on the left side that work equally well in the murine system and we put them in the NHP system on the right side, you can see that there's actually a substantial difference in the amount of brain uptake we're able to drive.

All of them work in the sense that they drive significant increase, but there's working tenfold and then there's working 30-plus fold, and we're looking really for the antibodies that work 30-plus fold. So that's where we're honing in.

And this is where the affinity uptake relationship is just -- seems to be different between the murine system and NHPs. And this will matter a lot when we get into the specific applications. So the first specific application I'll talk about is an anti-amyloid antibody that's enabled with ABC technology.

So in this case, we combine both the best-in-class anti-Aß epitope, which is the pyroGlu-Aß with our ABC technology. And in this case, we found it's very important to have fully active effector function in the constant region.

So we're basically using wild-type IgG1. We're not trying to ameliorate or cripple the effector function because we feel like basically every clinical molecule that's worked to clear Aß in the human patient population has had a fully active IgG1. Antibodies that do not have the fully active IgG1 have not been effective in patient populations.

And so whereas some of our competitors are trying to differentiate by fine-tuning or tweaking the Fc, we're going full rip on potency, and we're, again, fine-tuning the safety using our ABC epitope.

And just again, when we're highlighting the molecular features here, all of these antibodies are designed as highly manufacturable therapeutics, so concentratable to a very high level up to 150 mg per ml in this case, subcutaneous administration is definitely the ultimate goal with this antibody.

And given the amount of brain uptake we're able to drive and the very low dose that supports, we think this is the highly likely way to go and our clinical trial will go immediately into both IV and subcutaneous administration.

Just to talk just a little bit about the Aß side of our antibody. So it is able, obviously, to drive significant level of phagocytosis by microglia against the pyroGlu-Aß, which you see on the left side.

On the top middle, you see microglia phagocytosis of, again, the pyroGlu-Aß. If you can squint and notice, you'll see when we apply the ABC technology to the Aß antibody, we don't see any decrease in phagocytosis. We actually see a slight increase, a slight amount of additive phagocytosis, which is nice for us.

On the bottom middle, you can see light sheet imaging of a 5xFAD mouse that has been dosed with a murine surrogate of our AL137 lead antibody. So it has the same anti-Aß fab, but it's using an anti-urine TfR surrogate, ABC. And you can see there's no vascular staining.

The antibody is not stuck. It's really distributing and modeling exactly where the plaques are located across the brain. And on the right-hand side, you can see on the PD sense the ability of our antibody to drive reduction in Aß 42 species and Alzheimer's mouse model in this case of 5xFAD. This is again with the murine surrogate TfR.

At the time we ran the study, we didn't have the mice crossed with the human TfR with the 5xFAD. So skipping ahead a little bit to the nonhuman primate system. We did a 2-dose study in the nonhuman primates. This case, we're looking at CSF uptake.

CSF is not the perfect proxy. CSF is not actually where we want our drug to go. We want our drug to go into the brain parenchyma, but it is the measurement that we're able to look at rapidly in the clinic. So we want to make sure we're able to see this rapid uptake. And you can see even 24 hours after dosing, you're seeing a greater than 12-fold increase in antibody levels in the CSF with AL127 compared to the Aß antibody without the ABC technology.

And the difference is even more stark when you look at where we actually want the antibody to go. So this is brain uptake in what we call a vessel depleted brain fraction. So we've actually isolated the brains, different brain regions from these animals, did different [ centrifugation ] to remove the vessel fraction, and we're only looking at antibody that's fully crossed the barrier and is now in the brain parenchyma.

And in that case, we see approximately 30 to 32-fold increase in AL127 over the naked antibody. And the important thing to here is in addition to the vessel depleted fraction, we also look in the whole brain fraction in order to compare to some of our competitors. And we did absolute brain uptake.

And on the top left here, you can see we benchmark our antibody after a 3mg/kg dose as getting in at 8.4nM in the frontal cortex. And to put those numbers in context, we did literature search. We looked at some of our competitors were doing. We pulled out the Roche NHP data, and they're showing 2.2nM brain uptake after a 10 mg/kg dose. So we're seeing fourfold more antibody getting into the brain at a 3.3-fold lower dose.

So we're really driving a significantly stronger increase in brain uptake, not just compared to a naked antibody, but compared to other BBB-enabled antibodies. And we did similar comparisons for Denali's transport vehicle module for the J&J antibody and for BioArctic.

And in all cases, our antibody is driving significantly higher absolute level of brain accumulation, specifically at the lower dose. We think this has a lot to do with the affinity of the anti-TfR module that we're using and its specific sort of on-off kinetics.

We also, not shown on this slide, have a backup to AL137, AL037, which also benchmarks stronger than any of the other competitors that we looked at, but has a little bit different affinity to TfR, a little bit different performance in safety and serum PK metrics.

And importantly, because we're looking at a fully active effector function antibody, relatively high affinity to TfR, the safety readouts are pretty critical. In this study, we dosed AL137, not just at the 3mg/kg therapeutic dose, we also dosed at 30mg/kg tox dose. AL137 was well tolerated at both the therapeutic and the tox dose up to 30mg/kg.

As expected, we saw a transient reduction in the reticulocytes at therapeutic dose reticulocytes had fully recovered but for the next dosing interval, which is a week. And in the course of the study, we did not see any decline in red blood cells for hemoglobin, and we overall saw no test article-related adverse findings in any of the groups in the study.

So this is a molecule we are moving forward to IND by the end of this year, maybe slipping into early next year, and we hope to dose first in human relatively soon after that. To switch over to a second example, this is an ABC-enabled GCase enzyme for treatment of GBA and PD. And so in this case, we're delivering an enzyme GCase, which is implicated in pathogenesis of Parkinson's disease and Lewy body dementia.

This is actually in terms of lysosomal enzyme or lysosomal storage disorder, a relatively large patient population. It's a very attractive genetic target where a double knockout of the enzyme leads to Gaucher disease and a single knockout leads to the GBA deficient PD. So it's a genetically defined target characterized by loss of enzymatic function, relatively clear path forward.

The reason it hasn't really been addressed to date is there's 2 main challenges. One is just delivering an enzyme across the blood-brain barrier into the lysosomes of cells where it's needed. And the other one is for anyone who's worked on it, GCase is a very finicky, difficult to produce enzyme. So we had to sort of overcome both of these at the same time.

So in my group, we engineered a version of the GCase enzyme that's approximately 50x more active than the wild-type enzyme and that has a stability in serum-like conditions that's increased from less than 6 hours for the parental enzyme to over a week for the engineered enzyme. And then we took that and paired it with a specific flavor of GFR ABC that's designed to both drive uptake into the brain and into neuronal cells in the brain to put together our final AL050 molecule.

And in this case, we can get an additional layer of safety by pairing our ABC TfR epitope with inactive Fc. So to look in the murine system in wild-type mice, so these are mice on the left that don't have any deficiency in GCase with, again, a murine surrogate, we're already able to see 100% increase in GCase activity.

This is already more than the 50% that we would need to see to normalize heterozygous GCase patient. We're able to see significant reduction in the accumulation of toxic substrates, in this case, glucosylsphingosine in the GBA homozygous knockout mouse system. So you can't see knockdown of toxic substrates in the wild-type mouse because they don't have accumulation of toxic substrates.

The most important data to me is on the right side here, where after a single dose of the AL050 surrogate, we see sustained reduction in the toxic substrates far beyond what the PK of the molecule would look like. So this is an enzyme, it can clear relatively quickly.

But once we get into the cells into the lysosome, it's able to do its activity for far longer. And the reduction in substrates in this case lasted out well beyond 4 weeks, right? You can see at 4 weeks, we're still maintaining a 40% reduction.

So we took this molecule forward as well into the NHPs. In all of these case studies, I'm kind of simplifying everything. In a lot of cases, it took multiple rounds of murine and NHP studies to get to the final point. In this case, we're looking at enzymatic activity in the plasma just to confirm the increased stability and activity of our enzyme.

Other enzyme replacement therapies for GCase that utilize a wild-type enzyme have a half-life -- activity, half-life in the serum of minutes. We're looking at over 6 hours. So this is where you see that 50-fold increase in activity and stability.

When we look in the brain, we are seeing substantially increased brain uptake of the GCase enzyme when we apply the ABC technology to it. This is compared to what we call naked AL050, but it's just -- it's the enzyme that's on the same backbone. It has the Fc. It just has an isotype control fab so that we're not using -- seeing binding the TfR.

And in this case, we see increased uptake from 5 to 18-fold. But I think the really important data here is the amount of enzymatic activity we're able to drive. So these are healthy wild-type monkeys. They have no deficiency in GCase enzymatic function. So they're already starting at 100%.

So in this case, our bar would be to see a 50% increase over the 100% wild-type function in order to give us what we would need to increase a heterozygous patient up to wild-type levels. And in every brain region we test, we see significantly higher than this. So we're actually seeing between 63% and 132% increase in enzymatic activity.

And the increase in enzymatic activity is actually higher than what we see in the increase in just enzyme level when you compare both total endogenous so GCase and our introduced GCase, which is, I think, reflective of the higher enzymatic activity of our engineered enzyme.

And this molecule is also well tolerated in NHPs, no AL050-related clinical signs. There was no impact on hematology. In this case, there was not even any transient reduction in reticulocytes. Again, in this molecule, we have double protection with our ABC epitope and the silence Fc.

So basically, there were no test-article related adverse events at all. And then just to quickly introduce our ABC platform. So we realized quite quickly that our platform as well as enabling protein-based therapeutics is also a great platform for delivery of siRNA therapeutics.

So I'll show a little bit of data in a murine study we did with a SOD1 proof of concept, but then we very rapidly moved to applying this to therapeutic targets, including TAU, a-Synuclein and NLRP3. So this utilizes a format relatively similar to the GCase.

In a lot of ways, the mechanism is similar between the enzyme and the sRNA because we're using ABC to drive it across the blood-brain barrier, but also into a cell type of interest. So this requires a certain flavor of TfR, relatively high affinity. Again, allows us to use the silence Fc to get a little bit better safety.

In this case, on the siRNA cargo side, we partnered with an industry leader, AKSO Labs, to allow us to very rapidly develop siRNAs that are very highly potent, very highly specific. And then again, obviously, the main point of using the antibody delivery of the siRNA is to get around the current brain delivery of siRNAs, which relies on inconvenient routes of administration, such as intrathecal.

So all the data we'll be showing with peripheral amounts of administration, such as IV and subcutaneous. So in our proof-of-concept murine study, we did a multi-dose IV study. This was modeled after the OTV study [ eBarker ] at all 2024. So multiple IV doses compared to an ICV dose.

And it's not labeled on the slide, but the ICV dose siRNA also included the Alnylam C16 modification to make sure that we are doing an apples-to-apples comparison and showing the strongest brain knockdown. And in every brain region we tested, the IV dosed ABC-enabled SOD1 siRNA actually showed stronger brain knockdown than the ICV dosed siRNA with the C16 modification.

So we thought this was pretty good proof of concept. Again, at the same time, we're developing anti-Tau, anti-a-Synuclein, anti-NLRP3 siRNAs that are, as you see on the left side, highly potent. So this has an IC50 of about 21 pM and transfection model. It knocks down all the different isoforms of Tau in the neuronal setting, it is also active in [ sino ] cells. And then on the right side, you can also see activity in neurons and a passive uptake. So the first 3 on the left are with the unconjugated siRNA.

The one on the right side is actually with the final conjugated molecule with, in this case, using the ABC to drive the cell uptake instead of using an artificial transfection type system. So the molecule is active in both settings.

And then when we look at, again, performance in the NHPs, we're able to see very strong accumulation. This is a repeat dose, 3 x 3 mg/kg siRNA equivalent study modeled after an Arrowhead study. And in this case, we're seeing uptake of 40 to 130 nM of siRNA into different brain regions. And this is one of the advantages over other delivery routes such as intrathecal. When you dose siRNAs intrathecally, you can see very high local siRNA levels in some brain regions, but you can see a difference of 10 to 30-fold in other brain regions.

And in our case, because we're delivering through the capillaries, you see a much more widespread bio distribution. And this leads then to a knockdown of the Tau mRNA of up to 70% in different brain regions. And then looking at how mRNA level knockdown corresponds to what we're actually looking for, which is protein level knockdown.

On the left-hand side, you can see knockdown of Phospho-Tau 217, which is one of the toxic Tau species now at the protein level, and we're seeing knockdown of 43% to 64% at day 28.

Day 28 is probably not where we're seeing the full knockdown effect because if you know the Tau system, the turnover of the protein itself is around 20, 22 days. So you're starting to see the protein being knocked down here. On the right-hand side, we can see some CSF Tau data.

Obviously, the CSF Tau is a lagging indicator. But as we took the study out longer out to day 49, out to day 70, we see up to about a 50% decrease in the Tau, the protein level in the CSF. And then as well in the study, we did both therapeutic dose. We also did a very high 30mg/kg siRNA equivalent tox dose, again, to move this molecule forward as an actual therapeutic.

Even at the high tox dose, we saw no adverse events. We saw no effects on hematological tox parameters such as reticulocytes or red blood cells. So again, this molecule is very well tolerated at doses up to 30mg/kg siRNA, which when you convert to a total dose is very, very high. So this is a really safe platform, we think, for delivery of siRNAs.

We also saw no increase in liver enzymes or inflammatory proteins. So very safe across the board. And I believe I've left exactly 5 minutes for questions.

All right. Well, thank you so much, Eric. lots of really interesting science here. Maybe we'll address that with a couple of questions. And then I do want to ask a couple on the clinical side as well. So you've got 2 or 3 cargoes here, one an antibody, which combined via 1 of 2 catalytic arms. You've got an enzyme, which kind of has small molecule catalytic activity.

And then you've got an siRNA, which targets within like intracellular nucleic acids. All of that is limited by brain penetrants. How are you thinking about dosing across 3 very different modalities? And how does that -- how might that look from a potential -- you mentioned a subcu goal with the Tau antibody -- sorry, with the amyloid beta.

And then yes, and then in terms of the other platforms as well?

Yes. So I should have said subcutaneous administration is a goal for all of these programs. For the Aß drug, I think we have a very clear path to that. We've already mapped out. Dr. [indiscernible] team has done some modeling studies to show we should be able to get sufficient coverage of our drug even at doses well below the 3mg/kg dose that we showed here. And that would give a total dose level that's very amenable to subcutaneous administration.

For, say, the GCase cargo, it is still a goal. We've worked -- even though it's an engineered enzyme, we are able to concentrate it quite high, but the ability to dose it subcutaneously will really depend on the final efficacious dose that we need to move forward into the clinic. And as well for the siRNAs, we're working hard to enable a subcutaneous dose.

Got you. And then maybe I might ask Giacomo a question, if you don't mind. So in terms of maybe the path towards the IND and the plan to submit that IND in potentially Q4, maybe Q1 of '27, what does that timing look like? How many patients are you thinking in the dose escalation and extension arm? And maybe what you might present as an initial readout?

Sure. Thanks. So as you said, the time line to IND is Q4 this year or Q1 2027, depending on the availability of the clinical supply. We plan to start in healthy volunteers with a single ascending dose study which will also have a subcutaneous arm and the subject that we plan to enroll are the standard number of subjects in any other SAD. But then we want to quickly pivot to the MAD that will be done straight in patients with early AD, so MCI and mild AD.

An important readout will be the degree of amyloid clearance as measured with amyloid PET. We know this to be a very sensitive marker. And with effective drug, we believe we're going to be able to show an effect only with 10 to 15 patients. The MAD part of the study will be heavily used as a subcutaneous formulation because the goal of the Phase I program is to be able to show decrease amyloid in the brain in patients with early AD with subcutaneous delivery without significant ARIA above background level of ARIA and without clinically significant anemia.

So that's the goal of the overall Phase I program. And we think we can execute it fairly quickly. We know where to go in terms of sites. We have done already many other studies in Alzheimer's disease. So we are looking forward to starting the studies in healthy volunteers and patients in 2027.

Makes sense. And how long is the follow-up?

So the follow-up will be pretty standard. I think meaning that if you look at trontinemab data, they are able to show almost maximum amyloid clearance by 6 months and a significant degree of amyloid clearance as early as 3 months. And the studies will be long enough to show maximal effect in the double-blind portion of the study, and this will be followed up by on open-label extension, so where we keep collecting biomarkers as well.

Maybe one more in the last minute. You have the interim analysis, futility analysis for the AL101 candidate coming up. It's either happened already or will happen soon. Is that going to come with a data readout? What are we going to see from that? And if the futility analysis is in H1, is that going to be early H2 that we're going to see that? Or is that early? Is that still around the May, June time frame?

So I'll start talking about the timing. The interim analysis will happen in first half of this year, and we will update on the -- when it happens. This will be done interim analysis by an independent data monitoring committee who will look at clinical efficacy measures as well as biomarkers according to prespecified criteria.

The outcome of the interim analysis will be binary, meaning the recommendation to stop the study for futility as the prespecified criteria have been met or the recommendation to continue the study as planned as specified in the protocol until completion, until the last patient out that is planned for the end of 2026.

So we will have no visibility on the magnitude of the effects or what drives actually the decision to continue the study as planned, if that's the case. If the study is deemed to be futile, independent committee will communicate to the sponsor the recommendation for futility and then we will stop the study and look at the data in detail.

Thank you very much. Thanks for joining us.

Ladies and gentlemen, the program is about to begin. At this time, it is my pleasure to turn the program over to your host, Alec Stranahan.

All right. Great. Thank you, operator, and thanks to everyone, for joining the session with Alector Therapeutics, part of our BofA 2025 CNS Conference. My name is Alec Stranahan. I'm senior biotech analyst covering SMidCap and Alector at Bank of America. And I have the pleasure of being joined today by the Alector management team, including Arnon Rosenthal, Co-Founder, Chief Executive Officer and Director; Giacomo Salvadore, Chief Medical Officer; and Neil Berkley, Chief Business Officer and Interim Chief Financial Officer. Thanks, guys, for being here.

Thank you for inviting us.

Great. Great. Well, let's jump right in. I mean there's a lot to unpack from the pipeline. But Arnon, maybe if you wanted to give a quick overview of the company, clinical programs and upcoming catalysts.

Yes, absolutely. So Alector is a neurodegeneration focused company. We are committed to find therapeutics for Alzheimer's disease, Parkinson's disease and other neurodegenerative disorders. We have so far taken 5 drugs to the clinic. We have an ongoing progranulin elevating drug in Alzheimer's disease. Proganulin is a risk -- loss of function is a risk for Alzheimer's disease and progranulin is actually a universal risk gene for neurodegeneration.

Loss of function of progranulin is associated with frontotemporal dementia with Alzheimer's disease, with Parkinson's disease, with ALS, with LATE, which is another type of late onset dementia. And we developed a progranulin-elevating drug. And together with GSK, we are now testing it in Alzheimer's disease and we are expecting to have an interim analysis of our Phase II study in the first half of next year.

In addition to the clinical program, we have multiple preclinical programs that are propelled by our blood-brain barrier technology. We have an anti-A-beta antibody drug that's targeted to be in the clinic next year. That's driven by our unique proprietary blood-brain barrier technology. We have a GCase enzyme replacement therapy that's propelled by our blood-brain barrier technology for Parkinson's disease and eventually Lewy body dementia.

More than 10% of targeted patients are associated with loss of function mutation in this lysosomal enzyme and up to 30% of Lewy body dementia is associated with the loss of function mutation in this lysosomal enzyme and we engineered the enzymes and optimize blood-brain barrier technology that enabled effective delivery to the brain as an enzyme replacement therapy for these brain disorders.

In addition, we have a whole portfolio of blood and barrier-enabled siRNA programs, including tau siRNA, alpha-synuclein siRNA and LRP3 siRNA. And we think that with peripheral delivery of siRNA, you can really expand the usage of siRNA, develop a safer siRNA and more effective siRNA that can distribute homogeneously throughout the brain. So we are, again, focusing on multiple types of neurodegenerative disorders with multiple drug modalities, and we have resources to really bring these programs to value-creating points.

Okay. Great. I think that's a great introduction. And maybe we can sort of piggyback off the R&D day that you guys hosted back in September and starting on the ABC platform since that was a major focus of that update. And I think most investors are familiar with sort of the limitations of prior approaches to delivering drugs to the brain. How is the ABC platform maybe helping to solve for this or help broaden the therapeutic window? And how are you thinking about building out the pipeline in terms of target selection, optimization, et cetera?

So conceptually, the sort of blood-brain barrier technologies enable the delivery of large molecules like antibodies, enzymes and nucleic acid to the brain at 10- to 50-fold higher concentrations. And this enabled the usage of sort of lower dose with peripheral injections. It enables like higher safety. And in many cases, like in enzyme replacement therapy and in siRNA, there is really actually no possibility with peripheral injections to get to the brain.

With antibodies which have longer half-life and they are more stable, you can get very small percentage of the drugs to the brain after peripheral injections and the approved anti-A-beta antibodies, for example, are naked antibodies. They are injected peripherally and they still get at enough doses to the brain to show therapeutic benefit. But with blood-brain barrier technologies, you can use up to, again, 10x lower dose and because the drug enters the brain through a different route, you increase the safety.

For example, the anti -- the naked anti-A-beta antibody shows a higher degree of [ ARIA ] of inflammation and blood versus leakage because they bind likely because they bind to a A-beta plaques on the large blood vessels with blood-brain barrier technology, at least the Roche antibody have shown that you reduce and practically eliminate this side effect. So again, blood-brain barrier technologies increased the amount of drugs to the brain, increase the efficacy because you distribute the drug homogeneously throughout the brand, even in deep regions that naked drugs don't get into, and in many cases, increases the safety.

So I think it's really revolutionized sort of drug -- sort of drug treatment for brain disorders and enables, again, drug modalities like enzymes and siRNA that were completely not accessible to the brain before with peripheral injection.

Yes. And maybe we can go a little deeper there on sort of around the technological progress that you guys have made just around the technology and how you're sort of achieving the blood-brain barrier penetrates that you're seeing in your preclinical models?

Yes. So we, as quite a few other companies are using the transferrin technology as a Trojan horse to transport antibodies, enzymes and nucleic acid to the brain. So the blood-brain barrier has transferrin receptors normally to deliver iron to the brain, which is a required nutrients. And basically, this technology hitch hike or just use this receptor and enable delivery of, again, enzymes, antibodies and nucleic acid to the brain.

Multiple companies are using these technologies, but there are significant subtleties that makes one -- some technologies better than others. So the main differences between technologies are sort of the range of transferrin affinity binding that is being used, the epitope on the transferrin receptor that is being used and the drug configuration, whether you use bivalent binding or a single valency, whether -- what do you use to bind the transferrin receptor.

And these differences have impact on the level of access of drugs to the brain. They have impacts on the durability of the drug in the serum like which impact the dosing interval, and it impacts the safety. Unfortunately, although TfR is very effective in getting drugs to the brain. They are 10x more transferrin receptors on red blood cells than on the blood-brain barrier.

So a lot of the drug actually goes to reticulocytes instead of to the blood-brain barrier. And if there is a lot of drug binding reticulocytes depend on the drug configuration, whether it has an active effector function or not, but it can cause damage to reticulocytes and that causes anemia. So anemia is really part of the sort of target mediated adverse effect of this technology.

So again, if you have to find a drug -- an epitope on the transferring receptors that reduces the anemia and you have to tailor the affinity, so enough drug gets into the brands, but the drug doesn't have enough time to bind reticulocytes to facilitate immune response against reticulocytes and damage. So we were able to really identify what we think a good unique epitope that reduces the ability to induce damage to reticulocytes.

And we have like 1,000-fold range of affinities that we can optimize different drug modalities to maximize brain penetrations and minimize adverse effects. And for example, with our anti-A-beta drug, we think that we are able to bring drug to the brain at like up to like 12-fold higher concentrations than competitors. With siRNA based on what we see from the literature, we can bring siRNA to the brain at more than 10x higher concentrations than competitors. And we think that we have significantly reduced anemia because of the epitope that we are using.

So we think that, again, not all transferrin-mediated blood-brain barrier technologies were created the same. And we think that will sort of -- time will tell in the clinic, but we think that we have a really exceptional technology that enable very good delivery of multiple drug modalities to the brain with very manageable safety profile.

No, that's helpful. And I do want to sort of ground the discussion in the different assets you've nominated so far. But maybe just to sort of frame sort of the breadth of the approaches that you're pursuing. And I think one interesting thing that came out of the R&D Day was just around the adaptability of the ABC platform. You've got the brain carrier, right, that allows for crossing the blood-brain barrier, but you're able to adapt the antibodies with multiple therapeutic arms or an enzyme cargo or a nucleic acid cargo. I guess maybe just quickly touch around the sort of medicinal chemistry piece that got solved for the platform?

Yes. So I mean the way we link the transferrin [indiscernible] to the drug to basically to create the shuttle combined with the cargo. We have a lot of flexibility in this like where we bind the transferrin -- like where we integrate the transferrin [indiscernible] with the cargo. And for each drug modalities, we do it differently. Like for antibodies means the transferrin [indiscernible] is at the sort of C-terminal of the antibodies away from the binding domain like from the action of the antibody. For enzyme replacement therapy, it's part of the arms of the antibodies and for siRNA, it's in a third place.

So we have enough flexibility. We optimize the drug configuration for each drug modality, and that's really important because we actually tested 5 different drug modalities -- the 5 different configurations for each drug modalities and it makes a really big difference on the ability to enter the brain based on the drug modality on the -- and also on the half-life in the serum and on the safety.

So the drug configuration is really part of the critical components of safe and effective transferrin-mediated technology. So again, we have a 1000-fold range of transferrin affinity that we are optimizing, we have multiple transferrin epitope binding domain that we are optimizing and we have multiple drug configuration that we are optimizing. And the 3 things together really enable us to create an optimized drug that's really dependent on the requirement.

And again, different drug modalities have different requirements like enzymes and siRNA have shorter natural half-life in the sea room, so you wanted to move to the brain faster. So you need a higher affinity compared to antibodies. Antibodies like A-beta or tau likely require the full effector function because you want to recruit the immune system to remove the A-beta plaques or the tau aggregate. So for -- if you need a fully functional effector function, you increase the safety risk for reticulocytes. So you need to find the TfR epitope that reduces the adverse effect. So again, it really depends what the drug modality is and what the drug requires, whether it requires [Audio Gap].

Sort of the history around A-beta targeting sort of feed into your design for your molecule?

Yes. So anti-A-beta throughout Alzheimer's have been around for like 25 years now, I think, and the first generation was completely ineffective because in some cases, people used like an inert effector functions in other cases, people use the wrong binding epitope to A-beta, but as you know, like more recently, there have been 3 anti-A-beta drugs were approved, 2 of them are on the market, and both of them are what I call naked antibodies. They are just antibodies without blood-brain barrier technology.

And these are sort of lecanemab and aducanumab and they both show significant reduction -- removal of A-beta plaques over a 6-month period and modest clinical benefit of 25% to 30% slowdown in cognitive decline over 18 months. The main liability of these drugs outside of the modest clinical benefit is that they are associated with higher level of what's called ARIA like meningoencephalitis and blood vessel leakage and especially in APOE4 positive, A-beta -- APOE4 positive Alzheimer's patients, which are the 70% of the Alzheimer's population. So the adverse effects are really a major issue for first-generation drug.

So as you know, like Roche recently came up with an anti-A-beta drug with the blood-brain barrier technology, transferrin mediated blood-brain barrier technologies. And so far, they were able to show that this reduces the ARIA-related adverse effect. It seems to be like to 0, like the level of ARIA that they report is indistinguishable from the level you've seen in untreated Alzheimer's patients. And they show a more rapid and extensive A-beta removal, which could translate to better clinical benefit.

So it's pretty clear that second-generation anti-A-beta drugs with blood-brain barrier technology will displace the naked antibodies. And then among the anti-A-beta drugs with blood-brain barrier technology, we will have to see what stands out like whether the level of antibodies that you get into the brain, whether the level of anemia and in the case of the Roche antibody, whether the level of the infusion reaction that require steroid treatment will really make an impact on the drugs.

So again, we think that we can really excel with our anti-A-beta antibody, we see that we can deliver very high concentrations of antibodies to the brain 10 to 12-fold higher than what was reported by competitors. So this will enable significantly lower dose and likely subcutaneous delivery. The lower dose will also be associated with lower safety issues like infusion reaction, for example.

So we think that our drug would enable subcutaneous delivery, which would be transformative for this class of drugs because having to go to infusion reactions every month is not convenient for patients. There are not enough infusion centers for all the alternate populations the compliance is low because of the requirement for infusion.

So we are really targeting sort of subcutaneous delivery at much lower dose, which will facilitate safety. And hopefully, our drug will not -- because of the low dose and the configuration of the drug will not elicit infusion reactions, which is a major liability for some of our competitors. And again, the anemia, like Roche seems to manage the anemia.

But again, we think that our epitope that we have chosen would have lower anemia than the epitome that competitors have chosen. And finally, we are like to bind the A-beta plugs. We have used the pyroglutamate domain, which is different than what sort of the Roche antibody is binding Roche. The Roche trontinemab antibody used gantenerumab, which is as a naked antibody was not as effective -- was not effective clinically. It binds generally the terminal of A-beta.

And we think that our epitope, as Lilly has shown, is the most -- is the strongest in removing A-beta as a negative antibody. So we think it will be even stronger in conjunction with blood-brain barrier technology. So we think that we have a really good combination of an optimal anti-A-beta epitope, a fully function effector function that would enable very profound removal of A-beta and transferrin binding epitope that has reduced anemia and can deliver drug to the brain at very high concentrations. So the combination of these features, I think, could hopefully makes it a best-in-class drug.

Okay. That's super helpful. Thanks for the really detailed overview of the program. You also have AL137. Maybe just speak to the optimizations that have gone into this antibody and where you sort of direct investor attention as you're targeting first human studies next year?

Yes. So we have a lead antibody, which is the 137 and a backup antibody. They have somewhat different features like one has -- both of them have really good rain penetration, like 4 to 12-fold higher than what we think competitors can deliver. One of them has a slightly higher risk of reticulocytes damage. So we have like balance between efficacy and safety. We are going for maximal efficacy because we want to move to subcutaneous and be able to use really low dose.

So our -- sort of our -- the drug that enters the brain best is our lead, and we'll see how it works in the clinic. And we have -- right behind it, we have a backup antibody in case we need to optimize the safety features. But we are, again, targeting to have our lead in the clinic in 2026. Giacomo can describe the clinical plan, but goal is to go to patients and to show A-beta removal and minimal ARIA and no like manageable reticulocyte damage and hopefully, no requirement like no issues with infusion reaction as quickly as possible.

Yes. I guess on that, do you think the study and maybe Giacomo can weigh in, do you think the study will be designed in a way where you could see dose symmetry maybe on ARIA just to get a sense of sort of the -- because it is an on-target right? If you can get a sense of sort of the biologic effects AL137. I guess just what is the information that you think will be gaining from the study, presumably efficacy is maybe a secondary there?

Yes. I think with -- thanks to the implementation and standardization of amyloid PET imaging, which is the gold standard pharmacodynamic measure for anyone studying anti-amyloid treatments in the clinic. We are able to show to investigate the effect of the drug on amyloid clearance relatively quickly and in a small number of patients, 10 to 15 patients are enough to have a good estimate of the amount of amyloid clearance. 10 to 15 patients and this is an ideal number to make it suitable for multiple ascending those studies.

So as early as in Phase I and together these very important information. You asked about ARIA. For ARIA, it's -- I think it's a similar reasoning because there is a background ARIA rate, there is 5% to 10% in patients with AD. However, the anti-amyloid treatment, the first-generation ones, aducanumab, lecanemab and donanemab were showing much ARIA rate.

So this -- and these figures that I talked about this 5% to 10% natural occurrence of ARIA, 20% to 40% ARIA rate observed with anti-amyloid treatments allow us to have a good grasp on the liability on ARIA of AL137 as part of the multiple ascending those studies as well. A cohort of 10 to 15 patients dosed with the drug already give us a good idea about the ARIA risk. And of course, the cohorts in the MAD can be expanded and one can get better and more precise point estimates to really allow us to choose the optimal dose to move forward.

So in summary, I think we -- looking -- considering amyloid clearance and ARIA rate, we can get meaningful answers in Phase I with multiple doses. So early in the development program without waiting for a proper Phase II study.

So ARIA occurs very early in the treatment after the first or second injection usually. So you can very quickly see if there is ARIA risk or not.

Okay. Okay. That's helpful. And maybe for the sake of time, we can move on to AL50. This is another ABC and GCase-ERT ABC for Parkinson's. Maybe to start, do you think the longer plasma residence and activity is a differentiating characteristic of this asset? And maybe put that into context of the gene therapies?

Yes. So just to recap over 10% of Parkinson's patients, up to 30% of Lewy body dementia patients are associated with sort of loss of function mutations in this lysosomal enzymes, GCase. Also all Gaucher disease patients are sort of caused by loss of function mutations in this enzyme. For the peripheral pathology of GCase, Gaucher disease, there are -- there is enzyme replacement therapy currently that works very effectively. But because the enzyme is very short-lived, like in minutes in the serum, it doesn't enter the brain.

So the Parkinson's pathologies or Lewy body dementia pathologies cannot be treated with care and enzyme replacement therapy. So we did 2 things. First, we engineered the enzyme itself to increase the half-life in the serum, as you mentioned, by an activity by 10 to 40-fold and we have integrated with our blood-brain barrier technology to enable to bring it to the brain. So yes, I think that the longer residence in the serum enables the drug more time to enter the brain.

So I think it's part of the mechanism of action. So I think there are 2 components, like longer resilience in the longer time in the serum that gives it time to enter the brain to the blood-brain barrier technology and higher resilience in general that enables the enzyme to trans cytose to the blood-brain barrier and then to go into the lysosome without losing activity.

So we tested thousands of enzyme -- enzymatic mutations to really have an enzyme that's resilient enough to stay in the serum, like hours instead of minutes to be able to enter the blood-brain -- the brain to the blood-brain barrier and then not only that, but also enter the lysosomes, which is the natural side of action without losing activity. And for this, we have to optimize -- we have to optimize both the enzyme itself and the blood-brain barrier technologies and now technology.

And now we have -- we were able to show in nonhuman primate that we are able to, with peripheral injection, bring the drug to the brain, to the lysosomes and retain activity. And we think that the nonhuman primates are very predictive for humans. So we think that we would have a drug for Parkinson's disease and other indications where brain efficiency in GCase are pathological.

Okay. Yes. And I think you've said that you're targeting first-in-human studies in 2027 for this asset. Obviously, you mentioned the opportunity in Parkinson's, but also Gaucher disease and Lewy body dementia. I guess how do you sort of prioritize the indications here? And I guess, what are sort of the data points you'll be looking for to make those determinations?

Yes, I can take this one. Parkinson's disease is the lead indication. It's a disease where there are only symptomatic treatments being approved and GK remains a very interesting target given all the genetic links that Arnon just mentioned.

We can -- I mean, we will start the Phase I program in healthy volunteers and then move early to investigate the effect of the drug in patients with Parkinson's disease and GBA1 mutation. We can definitely have a look into pharmacodynamics, measuring the effect on GCase where we expect to see an increase.

And then we can -- we also plan to look at marker of disease progression. These are more exploratory. But in the end, we can -- I think we can get a good grasp on the dose to be moved forward through the Phase I program, both in healthy volunteer patients as it pertains in pharmacokinetics and pharmacodynamic results. Then one of the issues with Parkinson's disease, of course, is the fact that the endpoints are very noisy.

So in the end, moving forward to the clinic, we will have to think about studies that will be -- we need to have a sufficient sample size to look at the effect of the drug as compared to placebo disease progression and make the decision on the subsequent steps.

But the main point that I would like to leave you with is the fact that there are clinics that have already patients with PD and GBA1 mutation or mutations that are typically are the databases and are ready for being enrolled in clinical trials. So we're going to have early data in patients, which are always valuable. I think there is in CNS, there is a shift towards having data in patients as early as possible, and that's the strategy that we are following.

Okay. Very helpful.

Yes. It's worth noting just quickly that even though we sort of it makes sense to start with Parkinson disease with the genetic mutations in GBA, there are biochemical data suggesting that elevating GCase will be beneficial also for the sporadic form of the diseases. Parkinson's patients even without the mutations that have low level of GCase or have a high level of the toxic lipids that accumulate if you don't have GCase have much faster disease progression.

So we think that even sporadic Parkinson's patients will eventually benefit from this drug and the same for sporadic Lewy body dementia patients. So we think that -- there are already over, I think, 100,000 patients with -- just in the U.S. Parkinson patients with the GCase mutations, but we could go beyond that like to the sporadic version.

Okay. And then last question I have on the ABC platform and then we can turn to 101. You've got a few siRNA ABCs as well against fairly well-known targets like tau and alpha-synuclein for Alzheimer's and Parkinson's, respectively. I guess why siRNA versus an antibody? And is this hedging to the other 2 programs that we talked about? Or would they actually be used synergistically as an end goal?

Yes. Sort of for both tau and alpha-synuclein, there is sort of good rationale for siRNA. The pathology of both tau and alpha-synuclein is largely intracellular. Basically, the tau aggregates are intracellular and the alpha-synuclein aggregates are intracellular. So antibodies do not have access to the intracellular aggregates.

The idea for antibodies is that maybe they'll capture the pathological versions of and tau and alpha-synuclein when they sort of spread from one cell to another. If they go to an extracellular phase, it's not clear that that's really happening. It could be that even the spreading has happened through vesicles that are protected from antibodies. So there is really -- it's not at all clear whether antibodies that only capture the extracellular versions of tau and alpha-synuclein will be effective.

So far, there are several anti tau antibodies that did fail. It could be that they didn't use the right epitope, but it's very possible that siRNA or nucleic acid in general, will be more effective for these indications. And again, linking siRNA for tau alpha-synuclein with our blood-brain barrier technology will enable peripheral delivery, will hopefully ultimately will enable subcutaneous delivery and that really transform the accessibility to patients, like currently, the ASOs that are being tested for tau, for example, are having to be injected intrathecally. It's -- I think it's hard to scale up intrathecal injection to millions of Alzheimer's patients. The distribution in the brain is not homogeneous when you do intrathecal injection compared to peripheral injections.

So both with regard to safety, convenience and efficacy linking siRNA to tau alpha-synuclein with blood-brain barrier technology will be significantly superior. And I think siRNA will be superior to antibodies for these targets. For A-beta, it's not the same because A-beta is largely extracellular. So you can access it with antibodies, but these 2 targets are intracellular. So siRNA makes more sense.

Okay. Okay. That makes sense. Maybe we can shift gears and talk about AL101. Enrollment completed in this study in April of this year. I think you guys have guided to a first half readout next year. Maybe taking a step back, you have experienced developing and running a large pivotal study for Alzheimer's. You have experience developing a drug for a different indication, but same target, the PGRN target. I guess what are sort of the learnings that are being applied to the 101 program and then we can get sort of into the design?

So the one-on-one program is run by our partner, GSK, and we were able to leverage some of the learnings from the study that we did in Alzheimer's with AL002. The trial completed the enrollment ahead of schedule. So we knew where to go in terms of countries, in terms of sites. We already had experience on how make the implementation of amyloid PET and Tau-PET easier to implement in the context of a global Phase II study.

So from an operational standpoint, I think it was important to have this experience before, and this enabled a relatively quick enrollment. There is also quality aspects that we learned -- I mean, we implemented very careful oversight of the quality of the clinical endpoints, and this has been clearly also done here in the Phase II study with AL101, the Phase II study, which is currently ongoing.

Then other learnings are not directly related to our experience, but I think one of the pivotal moment for AD is when the data started coming out showing that a trial duration of 1.5 years, 76 or 78 weeks is enough to see an effect on key biomarkers of disease pathophysiology in AD. Even though the learnings were from A-beta molecules and here we are testing 101, which is not an amyloid removal drug. However, I think some of these things related to study design and duration are highly transferable.

And then of course, there is all the progress made with biomarkers through biomarker, all the p-Tau species, p-Tau 217, 181 that we understand more and more about the relevance, the relationship with amyloid PET, signal and Tau-PET and we are able -- better able to interpret what effects on those markers mean.

So I think we -- there were a lot of lessons that we -- lesson learned we implemented in AL101 Phase II study, and we're looking forward to the results of the interim analysis in the first half of 2026.

Yes. Yes. So where we -- and I guess maybe you can walk through sort of the primaries and the secondaries. I think CDR sum of boxes is being used again. This is what you've used in prior studies too, I guess, fairly well-regarded endpoint in AD. Is there a particular time point that you think is maybe the most impactful for understanding the potential for the program on CDR sum of boxes specifically? And then I guess, what are the secondary endpoints are you most focused on sort of for the potential in a Phase III study?

Yes, sure. I think previous studies have shown that for drugs that work in AD, there is the initial effects that may be appoint as early as after 6 months, but then the drug placebo separation becomes more apparent at later time points, namely 12 months and 18 months. The study duration of AL101 is 18 months.

So we are looking forward to the -- to see the effect of -- too see the effect of the drug at those time points that I mentioned. CDR sum of box is the primary outcome measure. We also have other composite endpoints that are used in this trial, such as the [indiscernible], for example, in the outcomes, and we're going to look at the effects on all those measures, knowing that all these CDR sum of boxes and the other secondary endpoints that I mentioned are not independent. They are -- they show some high correlation. So if you think about the results with lecanemab and donanemab, this show somehow similar effect on these different endpoints.

Besides clinical outcome measures, I also would like to draw your attention to the biomarkers that we implement in the study. We have amyloid PET. We have Tau-PET. We have fluid biomarker, the p-Tau species that I mentioned. So it will be -- those biomarker will be important besides the clinical endpoints to give us a more precise idea about the overall effect of the drug on the clinical progression of Alzheimer's disease and the effect on the biology of the disease through the biomarkers.

Okay. That's super helpful. I know we've got a couple of minutes left here, and I didn't want to finish without giving Neil a chance to talk about capital allocation. You guys ended 3Q with about $300 million in cash. I guess, how do you sort of see clinical programs and also the ABC studies being supported by this? And where does this sort of get you in terms of late-stage trials? I think you might be on mute.

So I think...

Maybe I'll start answering that.

So I think it may be working now. Is it working now?

Okay, yes.

Yes, yes. You are coming through.

Yes. Sorry. okay, somehow my mice muted. Sorry about that. Yes -- no, we do have runway through 2027 as guided, and we feel we're very well capitalized to advance multiple programs from our ABC platform as well as complete and execute on the 101 trial. We believe we will be able to achieve multiple value-creating milestones within the runway, including moving into patients and getting patient data with 137 as a key example and being able to move other programs to IND. So we feel good about our position. We have the runway to execute, and we believe that we have multiple shots on goal.

Okay. Very good. Well, I think with that, we're out of time. So we'll probably have to leave it there. But really appreciate the great overview of every -- all the exciting things going on at Alector, and thanks the team participating in our conference this year. Really appreciate it.

Thank you so much for the opportunity. Thank you.

Thank you.

Thank you.

Thank you.

Good morning, ladies and gentlemen, and welcome to Alector's conference call and webcast highlighting its progranulin franchise and Alector Brain Carrier programs. [Operator Instructions]

Now I would like to turn the call over to Katie Hogan, Senior Director of Corporate Communications and Investor Relations. Please go ahead.

Hello, everyone, and welcome to our event. Before we begin, I will go over a few housekeeping reminders. There will be a moderated question-and-answer session following prepared remarks. [Operator Instructions] The webcast replay of this event will be available tomorrow after 12:30 p.m. Eastern in the Investors section under Events and Presentations on our website, www.alector.com. I'd like to note that during this event, we'll be making a number of forward-looking statements, and you can find our disclosure here.

Turning now to the agenda. We'll begin with an overview from Dr. Sara Kenkare-Mitra, our President and Head of Research and Development. She'll share Alector's perspective on our multistage pipeline and our approach to driving value in treating neurodegeneration. Sara will then provide a review of our progranulin elevating franchise in FTD-GRN and Alzheimer's disease, highlighting latozinemab and nivisnebart, formerly AL101, which we are developing in collaboration with GSK.

From there, our Chief Executive Officer, Dr. Arnon Rosenthal, will discuss advancements in Alector Brain Carrier and introduce our lead candidates for Alzheimer's and Parkinson's.

With that, I'll now turn it over to Dr. Sara Kenkare-Mitra. Sara?

Thank you, Katie. Alector is dedicated to developing first and best-in-class disease-modifying therapies for neurodegenerative diseases with urgent unmet needs. We're building an integrated biotech that brings together expertise in genetics, immunology and neuroscience with deep capabilities in discovery, development and manufacturing.

Our therapies are designed to address the root causes of disease. Our 3R strategy aims to remove misfolded proteins, replace deficient proteins and restore dysfunctional immune cells and neurons. This strategy is powered by advanced technologies, including our proprietary Alector Brain Carrier, or ABC, which improves therapeutic delivery across the blood-brain barrier.

With our clinical late-stage progranulin elevating antibodies in partnership with GSK, a growing pipeline of ABC-enabled programs, strong cash resources and an experienced leadership team, we are positioned to drive both near- and long-term value. Our progranulin elevating programs form the foundation of our late-stage portfolio. Latozinemab in development for FTD-GRN has received breakthrough therapy, fast track and orphan drug designations, and top line Phase III data are expected by mid Q4 of this year. Alongside it, nivisnebart in Alzheimer's disease is fully enrolled in a Phase II trial.

In parallel, we have selected lead candidates for our ABC-enabled anti-amyloid beta antibody program for Alzheimer's disease, and our ABC-enabled GK's enzyme replacement therapy for Parkinson's disease. We are also progressing ABC-enabled siRNA programs for TAU, alpha-synuclein and NLRP3 for multiple neurodegenerative diseases.

This portfolio provides an important near-term milestone within our late-stage programs. It also includes the potential for the initiation of first-in-human trials from our ABC-enabled pipeline in 2026 and 2027.

Let me now turn to our GSK partner progranulin elevating franchise, which targets frontotemporal dimentia caused by granulin mutations and Alzheimer's disease. Frontotemporal dementia, while Alzheimer's disease is the most common form of dementia, you may be less familiar with frontotemporal dementia due to a granulin mutation, or FTD-GRN. FTD-GRN is an aggressive early onset dementia. Patients often present with compulsive behavior, lack of restraint, apathy, anxiety or aphasia. Tragically, life expectancy is typically less than 10 years, and there are no approved treatments to slow or cure the disease.

Heterozygous loss of function mutations in the granulin gene reduce the levels of a protein called progranulin by 50%, directly causing the disease. In partnership with GSK, we are developing latozinemab, which is designed to elevate progranulin levels back to physiologic levels.

FTD is rarer than Alzheimer's disease, but it is the most common cause of dementia in individuals under the age of 60, and most cases occur between the ages of 45 and 64. In the U.S., the prevalence is estimated to be approximately 50,000 to 60,000 people. And in Europe, the number is closer to 110,000. FTD-GRN accounts for approximately 5% to 10% of all FTD cases and represents about 8,000 to 17,000 cases in the U.S. and EU alone. Importantly, the overall economic burden per patient for FTD is nearly twice that of Alzheimer's disease, underscoring the urgency of developing effective therapies.

FTD-GRN is frequently misdiagnosed as Alzheimer's disease, Parkinson's disease, Lewy body dementia, vascular dementia or unspecified dementia, as you can see in the bottom half of the table. This underscores the importance of genetic testing to ensure patients are properly identified and can access future therapies. As we have seen in other therapeutic areas, once disease-specific treatments become available, the uptake of genetic testing typically increases. That means the landscape for FTD-GRN diagnosis could shift meaningfully as potential therapies move closer to approval.

Both latozinemab being developed for the treatment of FTD-GRN and nivisnebart, or AL101, being developed for the treatment of Alzheimer's disease are designed to increase progranulin levels by blocking sortillin, a receptor that binds progranulin and directs it to the lysosome for degradation.

Progranulin encoded by the GRN gene is a secreted glycoprotein which is primarily expressed in neurons and microglia within the central nervous system and has several activities, including being an immune and neurotrophic factor. Human and mouse data shown on the left side of the slide demonstrate that higher sortillin levels mean lower progranulin. By inhibiting sortillin, our antibodies increase extracellular progranulin levels.

The rationale for progranulin elevating drugs in FTD is clear. On the left, we show the 50% reduction in plasma and CSF progranulin in granulin mutation carriers and patients compared to healthy controls. This deficiency triggers a neurodegenerative cascade, neuronal cell death and microglial dysfunction leading to TDP-43 accumulation, lysosomal impairment, complement activation and inflammation. These processes result in destruction of brain structures, ultimately driving the cognitive and behavioral deficits seen in FTD.

Latozinemab is designed to elevate progranulin levels in the brain, addressing the underlying deficiency that contributes to neuronal loss, inflammation and cognitive and behavioral deficits in FTD-GRN. The rationale for progranulin elevating drugs in Alzheimer's disease is also compelling. Human genetics show that loss of function mutations in progranulin increase Alzheimer's disease risk, while preclinical studies demonstrate that elevating progranulin can be protective.

On the left, human genetic data highlights granulin as a risk stream for Alzheimer's disease. In the center, immunohistochemistry shows progranulin embedded within amyloid beta blocks in Alzheimer's disease brain tissue, emphasizing its association with disease pathology.

And on the right, data from AD mouse models shows that increasing progranulin improves disease-relevant outcomes. These findings together provide strong genetic, pathologic and preclinical support for evaluating a progranulin elevating drug, nivisnebart, in Alzheimer's disease.

The genetic and biologic rationale for blocking sortillin to elevate progranulin in FTD-GRN is grounded in multiple lines of evidence. Loss of function mutations in SORT1 lead to chronically elevated progranulin in humans and mice with minimal or no discernible adverse effects, providing a strong genetic foundation for this approach. Biologically, progranulin that does not bind sortillin can still enter lysosomes through alternative receptors, where it remains partially active and supports neuronal survival.

You can see this in the images on the upper left. Even in SORT1 deficient cells shown in the bottom panel, progranulin continues to traffic to lysosomes, similar to wild-type cells in the top panel. The schematic next to it illustrates how multiple receptors facilitate lysosomal entry in the absence of sortillin. Importantly, progranulin that is mutated to bypass sortillin appears more potent than wild-type progranulin in rescuing microglial pathology, reducing NfL and correcting lipid abnormalities in mice. Experimental data further support this strategy. The graphs on the bottom left show results with nivisnebart, our antibody that blocks sortillin to elevate progranulin.

In this first panel, nivisnebart nearly eliminates functional sortillin, confirming target engagement. This is accompanied by significant increases in progranulin levels in plasma and CSF, as shown in the middle and right panels. And these findings demonstrate that blocking sortillin effectively elevates progranulin and restores key functions of progranulin. Together, these genetic, biological and experimental data establish a compelling case for sortillin -- targeting sortillin to increase progranulin and address neurodegenerative disease mechanisms.

It's important to note that latozinemab and nivisnebart target distinct regions or binding epitopes on the SORT1 protein. The PK/PD profile distinguishes nivisnebart from latozinemab. While latozinemab is being developed to be a treatment for FTD-GRN, nivisnebart properties could make it suitable to address a broader spectrum of neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Both latozinemab and nivisnebart have demonstrated a two to threefold increase in progranulin levels and have been generally well tolerated in clinical trials to date.

Turning now to clinical data in our progranulin elevating antibodies. I will begin with our INFRONT-2 Phase II study of latozinemab, which was designed to gather data on safety, PK/PD clinical outcomes and biomarkers. In the trial, 12 symptomatic FTD-GRN patients were treated with latozinemab at 60 mgs per kg every 4 weeks for 49 weeks. To determine whether there was treatment-related slowing of disease progression, we used historical data from the GENFI2 and ALLFTD noninterventional registry databases to generate a matched control cohort that would allow us to make comparisons to FTD-GRN participants in our open-label interventional cohort.

In INFRONT-2, we evaluated 3 areas: target engagement through progranulin levels in plasma and CSF; biomarkers of disease activity, including lysosomal function, inflammation, brain health and atrophy, as well as clinical progression measured with CDR plus NACC FTLD, a tool designed for FTD.

We'll now review some of the key findings. In INFRONT-2 study, latozinemab increased progranulin in plasma and CSF two to threefold, restoring levels to those seen in healthy controls and sustaining them over 49 weeks. Also, plasma and CSF concentrations were strongly correlated, supporting the use of plasma progranulin as an important biomarker for use in clinical trials.

Here, we show the INFRONT-2 data for GFAP, or glial fibrillary acidic protein, a marker of astrogliosis that is elevated in symptomatic FTD-GRN and correlates with disease severity. These figures show that GFAP levels are elevated in symptomatic FTD-GRN patients at baseline and that at treatment, GFAP levels decline over the course of the study towards the range seen in asymptomatic GRN mutation carriers.

We also looked at disease progression using the CDR plus NACC FTLD, a measure of clinical progression in FTD agreed upon by the FDA and EMA. In matched controls from the GENFI2 registry, patients declined by 6.4 points over 12 months. By contrast, participants treated with latozinemab declined by 3.1 points over the same period, which represents an estimated 48% slowing of clinical progression compared to matched historical controls.

In INFRONT-3, our pivotal Phase III trial, we are measuring the same clinical measures and core biomarkers that we assessed in our INFRONT-2 Phase II trial. INFRONT-3 is a 96-week randomized double-blind placebo-controlled global trial evaluating latozinemab in 103 symptomatic and 16 at-risk individuals with confirmed GRN mutations.

Participants received 60 mgs per kg of placebo via intravenous infusion every 4 weeks. The primary analysis will be conducted in symptomatic participants, and we plan to include at-risk participants in a sensitivity analysis. The clinical co-primary endpoint is the CDR plus NACC FTLD sum of boxes. And in the U.S., the primary -- the biomarker co-primary endpoint is plasma progranulin.

Additionally, we are measuring key secondary outcomes, assessments and collecting fluid and imaging biomarkers, including plasma NfL, GFAP and volumetric MRI. We believe this positions us to deliver a clear and well-aligned data package later this year.

Our Phase II study of nivisnebart in early Alzheimer's disease is ongoing. In partnership with GSK, we completed enrollment of that study in April. An independent interim analysis is expected in the first half of 2026. PROGRESS-AD is a global, randomized, double-blind, placebo-controlled Phase II clinical trial enrolling patients with early Alzheimer's disease.

The study is designed to assess the safety and efficacy of 2-dose levels of nivisnebart compared to placebo. Participants are randomized to receive nivisnebart or placebo intravenously every 4 weeks for the duration of the 76-week trial. The primary endpoint of the study is disease progression, as measured by the clinical dementia rating sum of boxes, or CDR sum of boxes. We are also measuring key secondary endpoints and biomarkers, including amyloid PET, Tau-PET and biomarkers in CSF and plasma.

Our progranulin programs, latozinemab and nivisnebart, are being developed in partnership with GSK. This partnership included $700 million in upfront payments and includes a $1.5 billion in potential development and commercial milestones, a 50-50 U.S. profit share and tiered double-digit royalties ex-U.S. Potential milestone payments include $160 million for the first commercial sale in the U.S. and $90 million for first commercial sale in at least 2 of the EU countries.

With that, I'll turn the call over to Arnon to discuss our preclinical programs enabled by the Alector Brain Carrier.

Thank you, Sara, and welcome, everyone. I will now guide you through to a tour to our imminent future, which is propelled by Alector Brain Carrier. Alector Brain Carrier is using the transferrin receptor on the blood-brain barrier endothelial cells to deposit and transport cargo to the brain.

There are 3 features of Alector Brain Carrier that are worth mentioning. First is that our brain carrier module is completely independent. It can be placed in multiple places on the target. On the left here, you see replacing the brain carrier on the constant region of the antibody with a linker. The linker can be at any size or no linker at all. In the middle figure, you see us placing the brain carrier model as part of the FAB configuration.

And on the right, on the bottom, you see that we can place the brain carrier as part of a single-arm antibody or as part of an FAB. Our brain carrier can be bivalent, as you see on the left bottom, or monovalent. So this flexibility really enable us to tailor the drug to the different drug modalities, be it antibody, enzymes or nucleic acid. The configuration of the drug really dictate there, the drug half-life, immunogenicity and brain penetration. So this is an important tool to optimize blood-brain barrier propelled drugs.

The next feature of Alector Brain Carrier is the large variability or the large range of affinities that we can deploy. As you see on the left table here, we have almost 1,000 full range of affinities from 5-nanomolar to almost 5,000 nanomolars. And again, the affinity dictate hematologic adverse effects, drug half-life and brain penetrants. And this large range of affinity enable us to tailor the affinity to each drug modality and specifically within each drug modality to each drug and gives us a really unique tool to optimize ABC-propelled drugs.

The third unique feature of our platform is the epitope that they are using to engage the transferrin receptor. Whereas many many blood-brain barrier technologies are using an epitope which we consider to be exposed on the transferrin receptor, we have identified a different epitope that is depicted on the left side of the structure of the transferrin receptor. And this epitope is between 2 lobes. And the uniqueness of these epitopes is that it is reducing the ability of ABC propelled drugs to induce transferrin antibody-dependent cytotoxicity.

This is apparent on the right graph. And you've seen in the red line using the exposed epitope, what we call an epitope B, which many other companies are using. And this enables the antibody to facilitate ADCC that is transferrin receptor dependent. In contrast, when we use our own epitope, that's depicted on the graph in green and yellow here on the right, and you see a significantly lower ADCC. And this really provides a unique safety feature for our drugs. And we think that reduced ADCC would translate to reduce hematologic adverse effects and increased safety of our ABC module.

With these ABC features, we are developing, as Sara mentioned to you, 3 types of drug modalities. We are developing antibody drugs that are propelled by ABC, enzymes that are propelled by our ABC, as well as multiple siRNA that are propelled by ABC. I will start by describing our antibody against the beta amyloid that's ABC enabled.

Every aspect of our anti-A-beta antibody, which we designate as AL037, was engineered to optimize efficacy and tolerable pharmacokinetics and safety. So the anti-A-beta binding epitope was engineered to recognize the pyroglutamate version of the A-beta peptide. As was shown by Lilly, the targeting the pyroglutamate beta was the most effective in reducing A-beta plaque rapidly. And there is now A-beta pyroglu in the circulation in the serum. So this is minimizing sync effects and retention of the antibody in the periphery.

We undertook or chosen to retain a fully function -- fully functional effector function. We think that recruiting myeloid cells through the effect of functions is critical to fully remove beta-amyloid plaques and that effector function cannot be substituted by the transferrin receptor or by a crippled effector function. So we are targeting to maximize removal of A-beta plaques with a full effector function.

We then added to this drug, our optimized ABC technology, which is designated to maximal brain penetration and minimal hematologic adverse effects as well as maximize pharmacokinetics in the serum. And I will now show you some data with this drug. The first thing that we did is to confirm that AL037 can really transcytose through brain endothelial cells. And on the left side, you see a cell culture assay with brain and endothelial cells where you can put the drug on the top on the epical side, the blood side, of the culture. And then you can measure how much of the antibody can move to the basolateral sites, the brain side.

You can see in the middle panel here that naked AL037, this is an antibody that does not have the ABC module, that is not able to cross through the endothelial cells. In contrast, AL037, which does have the ABC module very readily being transduced through the endothelial cells. And this is quantified on the graph on the right. A very significant part of the antibody reaches the basolateral of this culture -- of this transwell culture, suggesting that it will be able to translate those to the brain in vivo.

The next thing that we confirmed was the ability of AL037 to phagocytose A-beta peptides. And on the left side here, you see images of human microglia phagocytose in fluorescent A-beta and internalizing it. And again, you see that AL037 is very effective in phagocytose in A-beta. On the right side, there is a quantification of this phagocytose is efferent. You see that naked AL037 in orange here can phagocytose A-beta plaques but the blue, which represents AL037 with the ABC module can phagocytose's A-beta plaques even better. This suggests that ABC module can contribute to phagocytosis, but it's still incremental and you still require a full effector function recruiting the A-beta gamma receptor for full phagocytosis.

We next move in vivo. We first tested AL037 in mouse models of Alzheimer's disease. This is the 5xFAD mice. You see on the left picture, this is a light microscopy. You see that the naked antibody primarily get stacked in the ventricle, in the large blood vessels and is not distributed well into the brain.

In contrast, the 3 right graphs shows antibodies that are enabled by our ABC. And in all cases, you see that there is no longer stickiness into ventricles and blood vessels, there is homogeneous distribution in the brain. On the 2 right panels you see that our antibodies can detect A-beta plaques very well and really bound to them. The most right pictures show a 3-dimensional constitution. You see antibodies recognize practically all the plaques in these brains or many of the plaques and can sort of recognize and bound to them.

AL037 not only bound to plaques, it also stimulate microglia dependent removal of plaques, and this is seen on the graph on the right, you see that even after 3 to 4 injection of the antibody, in a very short time frame, you see significant reduction in the level of A-beta 42 in the brain. So antibody at fairly low doses is able to penetrate the brain, distribute homogeneously and remove A-beta 42 in a very short duration.

With the mouse data at hand, we advance to nonhuman primate studies. The first thing that we looked at was the half-life of AL037, and you see in 2 doses, 30 mg per kg and 3 mg per kg. We see that the half-life of AL037 which is linked to our ABC is about 106 hours. This is significantly better than reported. Brain shuttle linked antibodies, and it's actually not far off from a naked antibody like a normal antibody. So we do show a very decent half-life of the antibodies in nonhuman primates.

The next thing that we looked was -- at was hematologic side effect. As you know, there is 10x more transferrin receptor expressed on the reticulocytes compared to endothelial cells. So all brain shuttle technologies that are using transferrin receptors have an inert risk of hematologic side effects.

So we measure that. As you see on the left graph, we do see transient reduction in reticulocytes, but the reticulocytes recover very quickly within a day. And even after 2 injections at day 1 and day 8, we don't see a meaningful reduction in red blood cells in the middle graph or in hemoglobin in the right partner. So we see a very tolerable safety profile for AL037.

We next looked at brain penetration in the nonhuman primate. And to our delight, we saw very potent brain penetration. As you see on the left panel in the frontal cortex, even at 3 mg per kg, which would be around the range of probably clinical doses, we see 18-fold, an elevation in brain penetration, and we see it in every brain region that we tested. And here, we show just the front of cortex on the right. On the left, and hippocampus on the left, but there is a homogeneous distribution of AL037 in the nonhuman primate brain.

If you calculate the molarity of brain level, you see that our AL037 even at 3 mg per kg can reach a 3.8 nanomolar in the brain. And this is, according to our calculations, at least 5x higher than what was reported for other brain shuttle antibodies that are currently in the clinic. So we see a very potent high concentration in the brain that suggest that this antibody would be very effective at removing A-beta plaques in human.

Given the significance of Alzheimer's disease as an unmet medical need, we are developing a second anti-A-beta antibody, which we designate as AL137. This antibody is deploying a different ABC modality with high affinity. And we see that in this case, we can achieve 32-fold increase in brain level. This 32-fold increase can translate to 8.4 nanomolar even at 3 mg per kg in the brain. And this is over 12x higher concentration that what according to our calculations was reported for clinical brain shuttle anti-beta antibodies. So we have, again, an even more potent anti A-beta antibody, which have still very, very good pharmacokinetics and tolerable safety features.

To summarize what I've shown you on our anti A-beta programs, we have 2 anti-A-beta antibodies, AL037 and AL137, that target that pyroglu anti-A-beta peptide, which in our view and as was demonstrated by Lilly, is the most potent epitope for removal of A-beta plaque. We retain a fully active Fc region to enable full function of recruitment of myeloid cells to remove A-beta, and we have an optimized ABC module that can lead to high brain penetration, but still good hematologic safety and good pharmacokinetics. So we think that we have 2 uniquely important and safe antibodies that could really be best-in-class in anti-A-beta therapeutics. And we are targeting first in human in 2026.

The next problem that I will describe is our brain carrier-enabled GK's enzyme replacement therapy for Parkinson's disease and eventually Lewy body dementia. As you know, GKs or GBAs, the lysosomal enzyme that remove toxic lipids like glucosylceramide and glucosylsphingosine form cells. And if you don't have functional GKs, these toxic lipids accumulate and cause diseases. There are up to 10 million to 15 million people that have Parkinson's disease that carry the GKs mutations. This translates to up to 1.5 GBA mutation carriers with Parkinson's that are up to 2.4 million GBA mutation carriers that suffer from Lewy body dementia. And there is -- there are over 100,000 gaucher disease patients with the GBA mutation.

There is -- as you know, currently, there is enzyme replacement therapy for gauche disease which display peripheral symptoms, but there is no enzyme replacement therapy for Parkinson's disease or Lewy body dementia because current enzyme replacement therapy cannot enter the brain. And even if it enters the brain, the way it enters cells that does not allow us to enter, does not allow it to enter as nerve cells or myeloid cells in the brain.

Even though we are starting with a genetic mutation carrier, there is really good evidence that GK's enzyme replacement therapy could be also beneficial for the sporadic form of Parkinson's disease and likely Lewy body dementia. The reason is that if you look at all-comer Parkinson's patients, if you measure the level of GK's activity versus the rate of progress disease progression, you see in the yellow line on the left graph that people that have high level of GKs activity show low progression rate, whereas people that show low level of GKs activity in the dark line display very high progression rate.

And consistent with the level of enzymes, you see on the right graph here, in blue, people that have low level of the toxic lipids show slow progression rate, whereas people with Parkinson's, this is regardless of whether they carry the genetic mutation or not. People that have high level of the toxic lipids display very happy progression. Right?

So this really suggests to us that even in sporadic form of Parkinson's disease, GK's brain penetrant and GK's enzyme replacement therapy could be beneficial to slow disease progression. So as we did with AL037, we did for AL050, we engineered every component of the drug. We first engineered the enzyme itself, the wild-type GKs enzyme has very short half-life. It is very unstable and it's hard to manufacture. So we engineered GKs that is almost 30-fold more stable than wild-type item. You can see it on the table on the left bottom, you see the wild type enzyme has a half-life at 37 degrees of 6 hours versus 7 days of our enzyme. Likewise, we engineered the enzyme to have almost 50-fold higher activity. You see this is a logarithmic scale. You see the activity of the wild type enzyme versus AL050.

So we designed a very potent and stable engineered GKs as the first component of the drug. We then linked it to an optimal ABC that has a higher affinity that enables faster removal, a fast transport to the brain. And as I'll show you also, transport to cells and to the lysosomes in brain cells.

And finally, because we don't need to recruit immune cells, we silenced the effector function of this drug to minimize or eliminate hematologic related adverse effect. So we took this drug initially to testing in cell culture. And the first thing that we did was to confirm that AL050 can enter lysosomes in cells. As you may know, the peripheral enzyme replacement therapy is using macrophages, mannose receptor to enter cells. So current enzyme replacement therapy for GKs, the protein can only enter macrophages in the periphery. It cannot enter nerves cells, and it cannot enter microglia cells or other cell types in the brain.

So first, we wanted to see whether we can substitute the mannose receptors with the transferrin receptor. And we saw that this is indeed the case. You see here that our GKs that is propelled by ABC can enter the lysosomes and you see overlay of staining -- fluorescent staining with lysosomal markers like LAMP1.

So on the left side, we show that our GKs is propelled by our ABC can enter cellular lysosomes, and these are neuronal cells that the naked -- the regular enzyme replacement therapy for GKs will not be able to do. On the right side, we also looked at activity of the GKs in this lysosome. And we see that there is very potent GK's activity in this GKs-deficient neuronal cells.

And the level of activity is transferrin affinity dependent. So -- and the higher affinity the ABC model, the higher the activity. And you see that with affinity that we are using in the -- for the clinical program, we are easily exceeding the wild type level of GKs activity, which is marked in the gray horizontal bad on the right graph. So based on the cell culture activity, we found out that we have a very potent and active enzyme. And we have a drug that can enter lysosomes in neuronal cells and can retain activity in neuronal cells.

With this information, we took our drug to nonhuman primate. We first test the half-life of our drug in the nonhuman primate plasma. And as you see on the left graph, AL050 display half-life of 5 hours. And this is compared to current enzyme replacement therapy that's sort of illustrated on the right side of this slide, current enzyme replacement therapy displays a half-life of less than 30 minutes. So in this experimental part in at least AL050 display tenfold higher, longer half-life in the plasma compared to current enzyme replacement therapy.

We then looked at the enzymatic activity in the nonhuman primate plasma. And we see on the left side here that AL050 delivered at 10 mg per kg peripherally, display half-life of activity of 6.6 hours. And again, this is almost 40-fold longer than enzymatic activity that was reported for current GK enzyme replacement therapy, where the serum half-life of enzymatic activity is less -- is about 10 minutes at the maximum even in human.

So at least with these experiments, we show that both in, in vitro biochemically in cell culture and nonhuman primate, we have a stable and an active drug that retain enzymatic activity extracellularly and will -- and sort of this will allow time for the drug to enter the brain and possibility retain activity in the rain.

And these are the things that we looked at next. And before we did that, we sort of looked at the safety of AL050. Again, all brain shutters that you're use transferrin as the Trojan horse have a risk of hematologic side effect. So we wanted to make sure that this is not the case with 050. You see on the left graph here, AL050 does not lead to any meaningful reduction in reticulocyte count after 2 injections. Likewise, there is no effect on red blood cell count and no effect on hemoglobin in this experiment, suggesting that AL050 will be safe with regard to hematologic adverse effects.

We next looked at what happens in the brain. So the first thing that we looked at was whether our ABC propelled AL050 can actually enter the brain, basically cross the blood-brain barrier and enter tissues in the nonhuman primate brain.

And we see that this is indeed the case. You see that in every brain regions that we looked at, the frontal cortex, hippocampus, as well as brain regions that are relevant for Parkinson's disease and Lewy body dementia, the substantial nigra where the dopaminergic cell, cell body design and the putamen where the dopaminergic and nerve endings are, we show very good level of AL050 that's sort of somewhere between 6- and 20-fold elevation of enzyme.

We then looked at enzymatic activity. And again, for enzymatic activity, our AL050 has to enter the brain, has to enter neurons and support us in the brain, has to enter lysosomes in these cells and then has to retain activity. So this is a very significant demand from drug, and we were not sure that this would happen. But to our sort of delight, it did happen. And you see that in all brain issue that we looked at, again, including the substantia nigra and the putamen, which are relevant, brain regions for Parkinson's disease and Lewy body dementia, we see at least twofold elevation in GK's activity.

Parkinson's patients and Lewy body dimensions have modest reduction in the GK activity, somewhere between 15% and 50% reduction. So doubling the level of GKs activity would be more than sufficient to fully repair enzyme deficiencies in these diseases. And moreover, we think that there is some negative regulation feedback on lysosomal enzymes. And so in healthy brains like in the nonhuman primate brain, high level of GK enzymatic activity could lead to reduction in the level enzymatic activity of the endogenous GKs. So we think that in patients, this level could be even higher. Although, again, as I mentioned, twofold elevation is significantly more than what is needed to fully restore GKs deficiency in Parkinson's patients and Lewy body dementia patients.

We then wanted to see whether our drug can actually correct disease pathology. And for this, we went back to mice. These are mice that carry the -- one of the Parkinson's GBA mutations, the D409V changes. And this mutation reduces GK's activity by 85%. So on the left bar graph, you see the level of GKs in wild type mice. This is in the gray. You see on the right side of the left panel you see that the mutation care -- the mouse mutation scares that were treated with PBS do not show hardly any GKs enzymatic activity. However, once we inject AL050, surrogate, we see almost complete restoration of GK's activity. And this is just 24 hours after 1 injection, you see almost complete restoration of enzymatic activity.

Now we went further and looked whether the increase in enzymatic activity is also associated with reduction in toxic substrates, and this was done initially in the periphery in liver. I'll show you data in the brain in the next slide. So again, you see on the right panel, the right graph, wild type animals do not have toxic substrates because the endogenous GKs get rid of them.

However, GBA mutation carriers have a very high level of toxic total, as you see from the blue bar graph here, but even sort of 2 injections of AL-050 that reduced these toxic substrates by almost 90%, suggesting that at least in the periphery here, our drug is very active, can enter cells and can restore enzymatic activity and can remove the toxic lipids that cause the disease.

We then wanted to see if the same thing can happen in the brain of this GBA mouse mutant. And what we found out is that this is indeed the case. You see on the left panel of bar graphs, this is still a wild type mice that carry the human transferrin receptor, but they have a wild type level or normal level of GKs. You see with PBS, this is the in gray. This is the normal level of GKs. But if you inject AL050 surrogate, you almost doubled the level of GK's activity in the mouse brain.

We then went to GBA mouse mutants. Again, in the middle graph, you see that wild type mice injected with PBS does not show any toxic substrates because the endogenous GKs take care of these. In contrast, mutant mice show high level of toxic substrates, as you see from the blue bar and single -- or 2 injections of AL050 surrogate reduce the toxic substrates by 80%. And again, the enzymes will continue to work. So 2 injections is a very short and acute time line. We think that over time, the reduction will be even more profound. Although 80% reduction in the toxic substract we think could be significantly therapeutic.

We wanted to look at the durability of the effect on the right panel here, and we see that even after a single injection, the reduction in the toxic substrate can last for over 14 days, suggesting that once our enzyme getting to the lysosome, it retains activity for multiple weeks, way beyond the residents in the plasma.

So just to summarize what I've told you, we have engineered AL050 to have multiple beneficial drug features. It has an engineered GKs that is 30-fold more stable and 50-fold more active than the wild type GKs that shows long half-life and long enzymatic activity in the nonhuman primate serum. We showed that AL050 can enter the nonhuman primate brain, enter nerve cells and support cells in the brain, enter the lysosomes and retain enzymatic activity.

So we think that we have a pretty potent drug that could be beneficial for, again, Parkinson's patients that carry the GBA mutations, Lewy body dementia patients that carry the GK mutations and eventually sporadic forms of these diseases. And we are targeting first in human in 2027.

I will just now describe our progress with Alector Brain Carrier-enabled siRNA programs. As you know, siRNA is becoming a very successful drug modality. I think that sort of there are over 20 approved sort of siRNA or ASO drugs now. Most of them are for peripheral indications. There are 2 nucleic acid drugs that are approved for central indications for ALS and for spinal muscular atrophy.

The issue for nucleic acid or siRNA for brain disorders is that you have to deliver it by IT or ICV injection, this is a surgical process that is not safe. It's not highly sort of scalable for large diseases like Alzheimer's disease. And also with IT or ICV delivery, the nucleic acid is not distributed equally throughout the brain. So some brain regions which are close to the injection sites receive more nucleic acid drugs, whereas regions which are further away from the injection site receive more deep in the brain and receive maybe insufficient drug.

So we are undertaking to change that by enable peripheral delivery of siRNA using our ABC technology. So we screened very extensively, as you see on the second from the left column, we screened very large range of transferrin affinities with different types of linkers, with different drugs and types of drug modalities to identify a good ABC carrier for siRNA. And this was really enabled by the versatility of our technology for -- where we can put the ABC module everywhere practically on the drug. We can use linkers or not use linkers, we can use cleavable or noncleavable linkers. We can use different affinity and we can use different valency. And this has really enabled us to optimize the siRNA delivery.

As you see on the third column from the left, we are able to achieve over 40-fold increase in siRNA delivery in the brain following peripheral injection. And the first thing that we did was to look at superoxide dismutase as a proof-of-concept strategy. And again, with siRNA to superoxide dismutase, we see with different ABC modules, we see 30- to 40-fold elevation of siRNA in the brain. And we also see, as depicted in the right column, very good long plasma half-life.

We then wanted to see whether our ABC propelled siRNA enters the brain, enters cells in the brain and enter the cytoplasma of the cells and is really able to suppress, to downregulate siRNA. Again, these are very demanding requests from a drug. We inject the drug peripherally. It has to go through the endothelial sales, like the 2 membranes of the endothelial cells to go through membranes on nerve cells and support sales and to enter to the right subcellar localization to access the messenger RNA for, in this case, SOD and to down-regulate it.

And to our delight, we saw that our drug is able to do that. If you see every brain region that we looked at, the thalamus, cortex, hippocampus, brainstem, cerebellum, spinal cord and striatum. In all cases, we see reduction in the SOD mRNA by up to 80%, and this is depicted by the purple and blue graph that represents -- as our peripheral injected siRNA with 2 different ABC modules. The purple graph represents ICV injected naked siRNA. And you see that in all cases, peripherally injected siRNA with ABC is at least as good as ICV injected siRNA. And in most cases, it's significantly better if you're seeing that cortex, in the spinal cord, in the brain stem, you see that our peripherally delivered siRNA is better than siRNA injected ICV.

So this really tells us that we could peripherally deliver siRNA, achieve homogeneous distribution in the brain, convert surgical procedure of ICV or IT into either -- easily deliver the infusion centers or ultimately even at home delivery with IV or even subcutaneous delivery. So we think that there is a significant potential for this technology to increase ease of use, safety and also efficacy.

With this technology, we are now developing 3 programs. We are developing TAU-siRNA with ABC for Alzheimer's disease and frontotemporal dementia that is caused by tau pathology. We are developing alpha synuclein siRNA for Parkinson's disease and Lewy body dementia. And we are developing NLRP siRNA for multiple neurodegenerative diseases.

As you know, NLRP is an inflammatory mediator that was -- that is start to be involved in practically every known degenerative disease, from Alzheimer's disease, Parkinson's disease, ALS, Huntington disease. And so far, small molecules for NLRP were not as effective in the clinic partially because of off-target activities and partially because of incomplete blockade. So we think that all of these 3 programs have a very profound potential in very large diseases.

Just to summarize what I've told you today and what you heard from Sara, we have a good mix of late stage and late preclinical programs at Alector. Our late-stage programs have a program in Phase III that is a pivotal Phase III where we received breakthrough therapy, orphan designation and fast track designation, and we will have data in the middle of Q4 2025. And because of the designations that the drug get, we think that we can proceed if the drug justifies that we can proceed to BLA rapidly and 2 commercializations. And we have commercial rights in the U.S., so we will be leading commercialization of this drug in U.S. as our partner will lead commercialization ex-U.S.

Our second drug, as Sara told you, is in early Alzheimer's disease. It's sort of completed recruitment. It's a 76 in April, 76 week long trials. So if you calculate, you see that trial completion is in 2026, and we expect to have data shortly after. In addition to our promising late-stage programs we have, as I described to you, multiple late preclinical programs that involve antibodies that are propelled by our ABC. I described the anti-A-beta antibody, but we also are advancing anti-tau antibody. We have enzyme that are propelled by ABC, for Parkinson's disease, Lewy body dementia and eventually gaucher disease with neurological pathology.

And we have an emerging platform of siRNA that are propelled by our ABC. These include currently siRNA for tau, for alpha-synuclein, for NLRP. But if successful, there are many more targets that would benefit from our ABC modules.

Again, as Sara described to you, we are completely focused neurodegeneration, and we are going after the core of the disease by developing tools to replace damaged or mutated proteins with enzyme replacement therapy, removing these other proteins with antibodies and siRNA and restoring damaged neurons and supported by antibodies that stimulate signaling in these cell types.

We have still over $300 million in the bank that will enable us to complete the 2 late stage programs and to take at least 2 of our preclinical programs to first in human. And we are targeting, again, to have multiple catalysts in post late and early-stage programs in the next 1 to 2 years.

So thank you, everyone, for listening, and we will now open the webinar for questions.

[Operator Instructions] First question comes from the line of Pete Stavropoulos with Cantor Fitzgerald.

Thank you for hosting this event. Very informative, and great to see you all, this activity across the pipeline. First question has to do with in INFRONT-3 as you have the Phase III reading out and it's top of mind. Can you just discuss some of the conversations that -- and data that you provided to the FDA that helped enable progranulin as a co-primary endpoint? And the sense that you received that they could possibly lean on it for an approval if clinical outcomes were trending in the right direction, but not to that take?

Thanks, Pete. I think I'll have Giacomo address this question. Giacomo?

Yes. Thanks for the question. The ask by the FDA to move progranulin as co-primary endpoint came as part of the review of the statistic analysis plan that we submitted several weeks ago. We didn't submit any new data to justify this recommended change by the FDA. Previously, in 2024, we discussed the use of progranulin as confirmatory evidence in addition to a single pivotal Phase III study, and the FDA agreed upon, and this is change that stemmed from this original discussion. But again, no new data were submitted by the company.

All right. Have you previously shown them, the correlation between plasma? Because specifically, the co-primary endpoint is plasma progranulin versus CSF.

We hadn't shown the correlation, but we had presented as part of the breakthrough designation package, the results on relation of progranulin in plasma and CSF that were comparable in magnitude.

All right. And 1 question, please, on the amyloid-beta ABC program, first in human trial in 2026. And I know it's early, but not in clinic yet. But curious to hear how you're thinking about clinical development sort of leveraging the data generated by approved amyloid data antibodies and those in development that can cross the blood-brain barrier easily with the technology. What would a proof-of-concept study sort of look like? And what would you like to see to move forward into late-stage programs? Would it be just imaging data or clinical data? And when it comes to safety, there were very low levels of ARIA for trontinemab. Does that molecule -- do you know if that molecule has an active Fc region? And what are your expectations for your amyloid beta ABC, will that translate to low ARIA rates in safety translate?

Maybe Giacomo can address the first part of the question, particularly in terms of what we believe a proof of concept would be for our anti-amyloid beta ABC.

Sure. The most recent data presented by other companies have shown that using biomarkers such as amyloid PET, it's possible to derisk anti-amyloid treatments relatively faster relatively early in the development program. So the current thinking is to use a similar approach and use extensively biomarkers, amyloid PET, as well as the [indiscernible] species in plasma to have information about the target dose and have an early read on pharmacodynamic effects that are important for therapeutic benefit.

Regarding the other question was about what we are expecting to see and will be. We will design studies to provide evidence of very meaningful and fast amyloid clearance but using both PET biomarkers as well as food biomarkers.

Yes. So just to add to this, there's a very clear path for anti-beta drug now, as Giacomo said, like we want to see profound reduction of A-beta plaques within 3 to 6 months, we want to see minimal ARIA. And Roche is also using a fully fund, so the full effect of function. So we don't think that, that will impact the ARIA. I think the ARIA is impacted by the way the ABC or the blood brain shuttle enters the brain. So we expect minimal ARIA, and we also are hoping to see a low level of infusion reactions, something that was not reported with sort of competing antibodies. So we think that there is very clear sort of proof of concept for a drug that can happen with a fairly small clinical trial fairly quickly.

Our next question comes from the line of Myles Minter with William Blair.

The first one on INFRONT-3 again. I know you've only enrolled I think it's 16 asymptomatic patients in INFRONT-3. It's not part of the primary analysis, but is there a path for those asymptomatic patients to get them on label if you do see positive data from INFRONT-3 in the symptomatic cohort? That's the first one.

The second, I'm curious as to the comment that the progranulin efficacy on lysosomal function is actually enhanced if it gets up taken through LRP1 versus sortillin one. If you could just expand on that because that is a source of investor concern, that you wouldn't actually get active granulin concentrations in the lysosome itself if you block SOD1? So that's the second one.

And the third one is just coming back to Pete's question, if you're going for fast amyloid removal with your amyloid antibody with the ABC carrier technology, is it safe to say that you'd want to see greater than 91% amyloid clearance at 6 months that we did see from the trontinemab data out of AAIC with the high dose?

Thanks, Myles. Maybe I'll address the first question and then pass it to Arnon to answer your progranulin biology question and to Giacomo on the anti-amyloid A-beta. In terms of INFRONT-3, as you asked, you're correct, Myles, that we have 16 asymptomatic carriers that we'll have data on. And as of now, we have not had any direct discussion with the agency in terms of label and what that data -- the impact of that data will be. As I said, we will be doing a sensitivity analysis based on data from these patients. And then depending on what we see, we would have further conversations on the label with the agency. I will pass it to Giacomo to speak about -- to Arnon to speak about the progranulin biology question first.

Yes, Myles. So this is a recent publication by an academic lab, where sort of they compared actually with sort of gene therapy progranulin. And that's mutated that does not bind sortillin and progranulin that can bind sortillin, and they show that the program -- like in mice that are deficient in endogenous progranulin, and they show that the progranulin that does not bind sortillin is actually more potent in multiple aspects. It can -- reduces neurofilament, whereas the wild type progranulin was not able to do that. It can reverse multiple lysosomal pathologies more potently that the wild type progranulin. It is surprising, but that's what they reported, and I'm happy to send you the publication.

And sort of -- that's a sort of second publication from this group showing the progranulin that cannot bind sortillin can restore both intracellular pathology primarily, again, lysosomal pathology in microglia and overall disease pathology.

Giacomo, do you want to address the A-beta question?

Absolutely. So Myles, we are very pleased to see the results as Arnon presented about effects of AL037 in the nonhuman primates, which shows very strong brain penetration. We aim with this program to show evidence of fast and very meaningful reduction of amyloid in the brain, along with the safety profile, which is favorable, meaning very low frequency of ARIA, no significant concerns around anemia and potentially a lower number of infusion-related reaction. And as well as developing a compound lens itself to subcutaneous administration as part of the development program.

Regarding [Technical Difficulty], we don't think that we necessarily need to be at a greater efficacy in removing amyloid and 91% that you cited with trontinemab. Alzheimer's disease is a very large population with a very significant unmet needs. And I think we -- I mean these are the goals of the program, not necessarily showing superiority, which I don't think is needed at this stage.

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

Thanks for the very informative session. I mean just to the last point, doesn't sortillin -- shouldn't a sortillin -- progranulin that can bind sortillin be more active, it's essentially stabilized. So doesn't it make complete sense?

Yes. In our mind, it does make sense. But as sort of Myles just alluded to, I mean, there is still raging debate in the field whether how essential sortillin is for the function of progranulin despite the fact that there are -- there is a wealth of evidence that progranulin can enter the cells without sortillin, enter lysosomes, retain functionality, both in cell culture and in mouse models in vivo. Despite our like Phase II data, the open-label data showing that all the parameters sort of going the right direction, cognition, biomarkers, imaging. So for us, it makes sense, but yes, it will -- hopefully, the actual Phase III data will convince the doubtful.

I get it. I get it. I get it. Okay. And then with all your work in shuttles, you must -- or it seems likely you've made either a shuttle direct progranulin or a shuttled sortillin receptor. Did either of them behave better in the gazillion assays you must be able to run? Or do you think 001 and 101 are, for you, going to be good enough forever?

Yes, we are sort of developing second-generation program. So everything that we do so far, we think that 001 and 101 are looking really good. Means the issue with enzyme replacement therapy for progranulin is controlling the dosing. Like progranulin is a growth factor. We have a built-in safety feature that we cannot elevate progranulin more than two to threefold, which we think is a sort of safe domain, like if you do enzyme replacement therapy, you can elevate progranulin in the periphery way more than that, and that could really lead to adverse effects. Means -- so we think that there is a safety issue like -- one of the companies that develop enzyme replacement therapy for progranulin had to sort of show significant adverse like immune-related adverse effects and have to use like immunosuppressive to deliver the drug.

Our drug seems to be very well tolerated, to the point that we think it will be applicable for prevention therapy if the data justified that. So, so far, we think that we have a really good drug, but we are always developing second-generation trial. We think that the target is [indiscernible].

And then the last 1 on the siRNA, you gave a relative amount of delivery relative to systemic to 40-fold. But do you know you have enough? You kind of know how much siRNA you need outside of cells in primates or something very close to humans. Do you know you're getting enough siRNA in? And in some sense, are you out of the woods with PK for siRNAs?

Yes, in the rodents, all the experiments we've done with equality with the ICV and peripheral injection. So we think that we get -- and we see over like up to 80% suppression of the SOB mRNA. So we think we are getting enough siRNA to the brain. We are sort of in the means of sort of not even primate studies, we'll see how it's translatable. But so far, what we see is that we can get enough siRNA both to peripheral tissues and to the brain.

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

Great event. This is Steven on for Yaron. A few questions here. So for the anti-amyloid beta ABC program, you mentioned first in human by 2026 and you discussed 2 molecules, AL037 and 137, which seems to be new. And you highlighted a few differences in the half-life. So what accounts for those differences? Is this -- are these 2 different molecules with different epitopes or is this same antibody with a different ADC carrier that might affect the PK/PD? And then secondly, just to clarify, are you still deciding between 037 and 137, which look pretty similar? And how would you make the decision of what to take into the clinic?

Arnon, go ahead.

Yes. Yes, the difference between the 2 antibodies is the ABC module, I mean, they have different affinity and the affinity dictate both the sort of level of brain penetration and the pharmacokinetics. So the difference in pharmacokinetics is sort of target dependent clearance in the periphery. So they have different pharmacokinetics. It's not clear what's the optimal peripheral pharmacokinetics for anti-beta antibody is. But we think that we have 2 very, very potent and promising anti A-beta antibodies that are driven by 2 variants of our ABC. At this point, we are advancing both of them. And if there will be -- we are continuing to explore if there will be data that will clearly point to 1 of them, we will advance one. But at this point, we think that both of these antibodies are very promising. They have different features that are worth examining, and we are committed to advance both of them at this point.

Understood. And maybe finally, you mentioned an interim data update on the business and PROGRESS-AD in the first half of next year. What can we expect to see from that in terms of patients followed or a time of follow-up?

So I can respond to that. The interim analysis planned in the first half of 2026, we haven't actually diverged the exact details of the interim analysis, and we shall be doing that in the future.

Our next question comes from Paul Matteis with Stifel.

This is Julian on for Paul. I appreciate you hosting this very informative event. Could you just describe -- have you ever shared beyond the 12-month data that you've disclosed for INFRONT-2, we've had 12 patients compared to the 10 patients in the longitudinal FTD registry data set. And if you have continued to follow patients, is there anything even qualitatively you can share about how these patients are doing or how the disease has progressed within them relative to natural history?

And then I guess, briefly, a second question. You talked about 5% to 10% of FTD patients having GRN mutations. If you were to guess, on which end of that range do you think most of the evidence actually supports? And how confident would you be in driving patient identification efforts? You talked about misdiagnosis in this patient population. So anything you can talk about that would be great to hear.

Great. Perhaps, Giacomo, you want to address the first question?

Sure. So as you mentioned, the Phase II study at 12 patients treated with latozinemab open label, and we have 10 mass control from [indiscernible] at 1 year. We -- the sample size is very small, and there are not the data, and -- there are not many data 2 years in the registries to support any kind of analysis as we did in 1 year. We have looked at biomarkers after 2 years. And the sample size is small, as there are -- not all the subjects who provide data at 1 year, were available for 2-year follow-up. This a very severely progressive disease.

But what I can tell you is that the drug appears to be safe, well tolerated. The biomarker effects that we saw 2 years in a smaller number of subjects are consistent with what we have shown at 48 weeks. And by mid-Q4 this year, we will present the results in a [indiscernible] number of patients, 103 symptomatic patients treated for 96 weeks. So we -- within this data will be the one that will be the most informative.

Arnon, do you want to add anything?

Yes, I can address the -- the second -- what's the second question? You can...

I think the second question was around the FTD range, the 5% to 10%.

Yes, the prevalence.

The prevalence. Chris, would you mind re-asking that question specifically?

Yes, relates on the range. So the fact is we don't exactly know, but as Sara showed you, up to 40% of progranulin mutation carriers are misdiagnosed. There's other types of neurodegeneration. So you think there is a fairly high level of misdiagnosis of progranulin mutation carriers that sort of don't fall into FTD. There was -- means a recent Los Angeles Times article on FTD that sort of put FTD as a very wide range of somewhere between 50,000 and 250,000 patients.

So that's something we think that we are looking at medical, Medicare sort of claims. And so we will have a much better idea on the prevalence, means that we will disclose at a later stage. But in general, again, as Sara said, that once there is genetic testing like available and once there is a drug, I think that the real prevalence will really come out.

Our next question comes from the line of Alec Stranahan with Bank of America.

Thanks for hosting the R&D call today. Maybe first on AL137 versus 037. You mentioned the reduction in reticulocytes between these 2 assets. Following up on a previous question that was asked, is this also a driver for which asset you'll take forward? And I guess, did reticulocyte levels recover in your preclinical model?

Yes, in general, safety is a parameter like what sort of was have shown with trontinemab is that sort of anemia is less of an issue than was initially thought. It's still, I think, up to 10% of the patients suffer from some level of anemia. In our nonhuman primates, yes, the reticulocytes are very sensitive to both multiple blood draws and to transferring dependent drugs. So there was a reduction in reticulocytes, but there was a roughly recovery. And the real measure will be long like chronic number of red blood cells and hemoglobin. And so far, we don't see changes in these. But absolutely, the safety will be a component of drug selection.

Okay. That makes sense. And then I guess, how do you think about 001 and 101 as monoclonal antibodies versus other MOAs such as gene therapies and development for FTD-GRN and maybe Alzheimer's as well? Obviously, noting that the others are a bit earlier in development.

Yes, sorry.

Arnon, do you want to?

Yes, I can take this. So as you said, both in terms of gene therapy, the small molecules, there is enzyme replacement therapy. They are both very early. So we are comparing some hypothetical potential to an actual like we are going to get pivotal Phase III data in a few weeks. So it's really hard to compare. But conceptually sort of the 2 gene therapy companies are struggling, means 1 of them could not show sustainable elevation of progranulin. Sort of basically progranulin was elevated for a few months and then sort of went down. The second company had sort of significant AAV-related adverse effects and again, has to use immunosuppressive drugs and to significantly reduce the dose.

And so the technical issues with gene therapy -- also, gene therapy is still, in fact, a small percentage of the nerve cells, and you assume that this small percentage of nerve cells will be a depot like will produce a large amount of progranulin that will then diffuse throughout the brain for the other brain regions. It's not clear how effective that is. And again, there will be a large disparity between some regions of the brain that have very high level of progranulin, other regions of the brain that have may be insufficient level of progranulin, it's not going to be a homogeneous distribution. And we offer the correct level of elevation. We offer homogeneous brain distribution. So we think conceptually at least that our drugs could be superior.

So the 2 gene therapies, again, have safety issues, I think, have durability issues. And I think we also could have efficacy issues that didn't really show any benefit outside of, again, transient progranulin elevation. Means the enzyme replacement therapy is still early. It was on hold for several months because of adverse effects. It's requiring again, immunosuppressive drugs to delivery. It's not clear how viable it will be. And again, it will be a big discrepancy between very high level of progranulin in the periphery versus -- we'll see if sufficient level of progranulin in the brain.

And there are also small molecule drugs that try to activate transcription from the progranulin gene. In the past, sort of these small molecules were tested and failed. And there is a small molecule drug that sort of blocks sortillin that's conceptually what we do with an antibody. And again, it's very early, so you don't really know the off-target activities. Progranulin and sortillin is a part of a very large family of sortillin receptors with very similar structure. So it's not clear what the off-target risks or adverse effects of a small molecule will be, what the durability will be and what the ultimate efficacy will be. So we think that at this point, we are in a very different place from competitors, both with how advanced we are and the scientific rationale for the program.

Our next question is from Graig Suvannavejh with Mizuho.

I just wanted to revisit INFRONT-3 real fast, just on the co-primary endpoints. Could you just remind us if you need to hit a p-value that's 0.025? Or do you -- is there room to hit 0.05 on both? I assume the former, not the latter. And as a follow-up, if you do end up seeing positive data, what are the gating factors in terms of next steps to be able to file a drug? If you could just remind us whether there are any CMC-related issues? Obviously, you'd have to meet with the FDA, but just trying to get a sense of how "quickly" you could actually indeed file for approval.

Maybe Giacomo can address the first question, and I can take the second part.

Sure. So we don't split the alpha for the trial to be positive. Both co-primary endpoints need to be met, and they are tested at the same time, not sequentially. So they both the CDR plus NAC as well as plasma progranulin, each, they need to be -- show a p-value that is less than 0.05.

Okay. I think in terms of just the BLA, et cetera, if the data are positive, we are already poised to be able to start working on getting the BLA filing going, and we are on track for any of the commercial manufacturing activities to do that in a rapid manner.

And just 1 last follow-up. With regards to any potential next opportunities with latozinemab, would you think about potential label expansion besides just potentially, the asymptomatic patients? I know a long time ago, there are interests and other indications as well for AL001.

Giacomo?

We are currently having those discussions, both internally and with our partner, GSK. So this is a very timely topic, and we'll disclose further details in the future date.

And we have a question coming from the line of Pete Stavropoulos with Cantor Fitzgerald.

A question on the scales to be used in INFRONT-3. For FRS, is this a more or less sensitive measure compared to CDR, sum of the boxes? Especially for certain, let's say, where you are within the disease stage, early versus later? We will be able to see different rates of improvement on FRS versus CDR over the 96 weeks of treatment? And is one better for asymptomatic versus symptomatic? How should we be thinking about that when the data comes?

Yes, great question. So most of the data that we have around the natural history, the natural progression of the disease are the one generated using the CDR plus NAC. The FRS, obviously, it's a scale of interest is an exploratory end point. The sensitivity and retail progression on the FRS are not very well known or described. So the -- hence, the decision to use the CDR as primary outcome measure, which is being validated in FTD as a whole and is the one that is recommended by the FDA. Will be interesting to see the results on the FRS, which is an exploratory outcome measure.

And we also, obviously, as you said, investigate the effect, I mean the change over time in presymptomatic as well as symptomatic subjects and the sensitivity to change over time. So it will be an important analysis.

Okay. And now I will transition back to Katie Hogan for any webcast question from the other side. Back to you, Katie.

Thank you. I think we have time for one more question that we received online. And this question comes from Sean at Morgan Stanley. And Giacomo, this question is for you. What are the key differentiators of latozinemab compared to other therapies and development for frontotemporal dementia due to a granulin gene mutation? And how do you see its potential impact on the standard of care? And we're specifically talking about Prevail Therapeutics and Passage Bio.

Thank you, Katie. I think Arnon already addressed these questions. And -- but I would like to highlight the fact that there are a lot of unknowns around gene therapy, what we know is the safety profile that doesn't look ideal. One company has reported only transit increase in progranulin letters in blood and in most patients, not on patients, which is very different from what we observed.

And then the other point is the rationale that a 50% decrease of progranulin levels are enough to elicit the disease frontotemporal dementia, mutation carriers. And with our approach, we are able to restore progranulin levels to normal levels, while it's a little bit more unclear, the rationale around the need to elevate, several fold higher than the normal levels.

Then going back to the safety, the 1 company showed increase in NfL that reflects the dorsal root ganglia toxicity, then the other company had immune adverse reaction. So there is quite some safety liability for the use of gene therapy currently, and that pertains around progranulin treatment, but also other forms of gene therapy.

Great. Thank you, Giacomo. That's our final question for today. And operator, I'll turn it back over to you.

Thank you so much. And as I'm not showing any questions at this time on this end, I will conclude the conference, and thank everyone for participating, and you may now disconnect.