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

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.