Alector, Inc. Aktie

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.

Good morning, everyone, and welcome to Morgan Stanley Global Healthcare Conference. I'm Sean Laaman, Head of SMID-Cap Biotech here at the firm. For important disclosures, please see 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 of hosting Alector's CEO, Arnon Rosenthal. So welcome and thank you for your time today.

As you said I'm the CEO and Cofounder of Alector. Alector was created to really address the major unmet medical need of neurodegeneration. As you know, 1 of 6 people in the world have brain disorder. And this is really one of the last major unmet medical needs like there are more than 50 million people worldwide with dementia, 10 million people with Alzheimer's disease and 1 million of people with other neurodegenerative disorders and we undertook to really find disease-modifying therapies for these major disorders by really going after the underlying mechanism of this disorder.

Great. I might just start with some macro questions. We're doing this for all our companies. But with China's rise in biotech innovation, how do you think about the competitive position here and will this influence your R&D or your business development strategy?

In general, I think that competition is good for everyone. I know that it's unpleasant at times, but I think that fair competition really raises everyone to do better, so I think I want to see the best drug for patients no matter where they are coming from. I think -- yes, the fact that China is becoming in a way, more innovative and more focused on pharmaceutical and biotechnology would really force the U.S. to do even better and I really hope that the regulatory environment will become more accommodating for the pharmaceutical industry and I think that just freedom and in a way, getting out of the way of the pharmaceutical industry will really lead to competitive innovation and will enable the U.S. to continue to be the leader in this field.

Great. And are you currently leveraging AI, if you are? And how about AI's disruptive potential. How do you think about that?

Yes. So we are -- we are excited about AI. We think that it's going to be a significant tool to facilitate both our discovery efforts and our clinical and preclinical development. And also, generally, the way the company is running even in the administrative aspect, so we have a team that's composed of research and administrative people that really dedicated to incorporating aspects of AI. And we are using all the many tools that are now available, like OpenAI and multiple programs that are dedicated to different aspects of science.

I don't think that AI is going to substitute thinking and science, but I think that it's going to be a tool to really facilitate science. So we are really embracing the opportunity, but we still think that old-fashioned scientific understanding and knowledge are still going to drive innovation in the foreseeable future. I don't think that AI for science still has enough information to really substitute scientists.

Wonderful one. I guess over the last period, like what's been the most impactful to Alector from the regulatory side? Would it be FDA and is probably bit too early or tariffs.

At this point, it's mainly the FDA. We have very close interactions with the FDA. We have a pivotal Phase III drug that received breakthrough therapy and orphan designation and that's going to read in the middle of Q4 this year. But if all goes well, we really try for BLA, and we'll consider commercialization. So interactions with the FDA on the statistical plan and on the approval process are what keeps us -- that's our main focus, but we are actually working internationally, like our manufacturing facilities are out of the country.

We actually also work with Chinese companies, so hopefully, the tariffs are not going to hinder our operation like longer term because again, I think that innovation requires global interaction. And basically, you should do the best thing wherever it's done best. And I think that we should facilitate freedom of interactions and like free interchange of both ideas and technologies and reagents and then hopefully, the tariffs will not curtail that.

Wonderful. Wonderful. And we get to Alector specific AL001, the company's programming on program for FTD-GRN. Can you give us a high-level overview of the program and what you and GSK hope the AL001 program can achieve?

Sure. So our most advanced drug, which is in pivotal Phase III and is going to lead in the middle of Q4 this year is targeting a disease called FTD, frontotemporal dementia. This is the largest type of dementia for people under the age of 60. It's 2 to 3x faster and more aggressive than Alzheimer's disease and it constitutes a major burden both for the patients and the caregivers because it is associated with this inhibition with regard to behavioral or with speech inability and motor disabilities and some form of cognitive disability and it's a lethal disease, people are diagnosed before the age of 58, and they die within 7 to 9 years.

So it's a very aggressive type of neurodegeneration. And currently, there are no approved therapies for this disease. And one of the underpinnings of the disease is a genetic mutation in a secreted immune-regulatory protein progranulin. People that have one good and one bad copy of this progranulin gene produced 50% of the normal level of the protein and they invariably develop frontotemporal dementia.

And we developed a drug called latozinemab or 001 that elevates the level of progranulin back to normal level in these patients. And the way the drug does it is by blocking the gradation cascade of this secreted protein. So what happens in patients, they produce half of the normal amount, but the amount that -- but the protein that's produced stays now in the brain 2x to 3x longer because it's not being degraded. And as a result, the reduced production is being compensated by increased half-life.

And conceptually, it's very similar to what all the SSRIs are doing like Prozac. Prozac prevent reuptake and degradation of neurotransmitters like serotonin and norepinephrine. And by that, it increases the level of these neurotransmitters in the brain leading to the antidepressive effect. We are doing the exact same thing. We increased the level of the protein in the residence time of the progranulin protein in the brain to 2 to 3x longer, and that's how we see the therapeutic benefit.

Wonderful. And how does frontotemporal differ from normal age onset dementia.

Yes. So frontotemporal dementia is different than Alzheimer's disease in the way that it's not really mainly shorter memory loss, it's more associated with behavioral abnormality, disinhibition, inability to control like behavior and also inability to articulate yourself to speak and eventually these people are unable to communicate, unable to control their behavior. They have extravagant behavior, they can go to people in the street and hug them and harass them, so it's more behavioral and speech abnormalities as well as motor deficiencies, which is different than Alzheimer's disease that's mainly like total memory deficit.

Got it. Just moving to the Phase III INFRONT-3 top line data, the readout is expected in Q4. So give us an overview of the trial design and what you expect to report in the top line results.

Sure. so as I mentioned, we are at the end of a Phase III study with this drug. It's placebo-controlled, double-blinded pivotal study with 106 symptomatic patients and 16 genetic mutation carriers that are still presymptomatic. And it's going to be a significant package of clinical and nonclinical readouts. We have the primary -- the co-primary readouts of elevating progranulin back to normal level or statistically significant elevation in the plasma. And the second co-primary is the CDR Sum of Boxes for FTD, this is a clinical readout that contains eight different domains of cognition, activity of daily living, behavioral and speech that we agreed with the FDA would represent the clinical readout.

So we have two co-primaries, progranulin elevation in the plasma and the clinical readouts. In addition, we are measuring multiple biomarkers, including neurofilament, GFAP and we are looking at change in brain, tissue loss in the brain with volumetric MRI. So at the end of this year, we'll have fairly extensive package that will tell us conclusively whether we have a drug and we agreed with the FDA that this single trial together with the biomarker will be enough to get approval.

And just to really double down on that, just to make -- talk about your alignment with the FDA on the endpoints and what gives you that confidence that the answer will be the answer.

Yes. So we -- again, because we received breakthrough therapy and orphan designations, we have very close interactions with the FDA. And recently, we agreed with the FDA that we will have, again, two co-primary elevation -- statistically significant elevation of progranulin, which is the disease-causing missing protein in the plasma and based on our open-label Phase II study, we think that there is more than 99% chance that we will reach this co-primary and we agreed with the FDA that the CDR Sum of Boxes, which is, again, tailored for FTD will be the clinical co-primary. So there is alignment that these two co-primaries will really drive the approval of the drug. And again, based on our Phase II study, we did show two to three-fold elevation of progranulin throughout the disease, throughout the treatment period, and we now have patients that have been treated for over 2 years.

And as long as the drug is applied to these patients, the progranulin level is restored back to normal level and indistinguishable from what you see in healthy individuals and with regard to the clinical readout in the open-label study, we were able to show a 48% slowdown in cognitive decline over 12 months with 12 patients. Our Phase III is 10x longer with like 106 patients, and it's twice as long with 2 years versus 1 year seen in the Phase II. So we think that we have significant room for variability and -- even though in the Phase II, we showed 48% slowdown in cognitive decline, we've seen that even if we show 25% slowdown in cognitive decline in the Phase III, it will still be statistically significant, clinically meaningful and in our view, approvable.

Wonderful. And could you remind us of a bit the time lines, how long the patients have been on therapy in the clinical trials and the time frames around measuring those endpoints.

So the trial is a 2-year long trial like 96 weeks. We decided to really follow these patients for almost 2 years to make sure that we can capture the disease progression and both the biomarkers and the imaging readout, we are measuring -- in the plasma, we are taking samples monthly. Like every time the patient is coming for treatment, we also taking samples of plasma, the clinical readout is every 6 months and imaging is also every 6 months.

Wonderful. And you presented INFRONT-3 baseline characteristics, the international study for FTD in September last year. Looking at those baseline data, how would you describe the FTD-GRN population involved in terms of at risk versus symptomatic and other clinical distinctions.

So in general, like the features of the patients that we recruited to the Phase III trial represents the general population based on what was reported in the major FTD consortia, both the European consortia and the U.S. consortia, so the general features of the symptoms, the stage of severity, level of biomarkers. So what we recruited, so the patient is really representing like real-life patient population and in the trial, we recruited two types of severity of disease severity, 70% of the population that recruited early-stage disease like CDR global score of between 0.5 and 1 out of a 3-point scale and about 30% is scale between 1 and 2.

So we have really very early patients and early medium patients, so we want to see the drug could work at these stages. And as I mentioned, we also have 16 patients that are still presymptomatic. And in this case, we want to see if we can prevent conversion from presymptomatic patients to symptomatic patients. And so far, the drug appears to be very well tolerated. It seems to be a really safe drug. So our ultimate goal is to really do prevention, to really capture patients before they become symptomatic and prevent the conversion to symptoms.

Understood. And I believe INFRONT-3 is powered to show 40% slowing of disease progression and KOL feedback suggests about a 25% slowing of CDR-SB would be clinically meaningful. Given that, what would be your expectations that the 96-week time point on CDR.

So again, our -- based on our Phase II, we did show 48% slowdown in cognitive decline over 12 months. So it means hopefully, the Phase III will produce this. But as you said, even 20% to 25% slowdown in cognitive decline according to the KOLs that we talked with will be clinically meaningful. This is a lethal disease. There's really no approved -- there are no approved drugs for this disease. It hits people at prime of their life, like when they are between 30 and 60. It's a major burden on the family because of the behavioral disinhibition. So we think that any even modest clinical benefit will be meaningful for this patient.

Wonderful. Maybe getting down to the nuts and bolts of building out a market model. So if you could talk about what the patient opportunity is here. And if the drug does prove successful, the touch points of how you go through the launch process, just to start.

Yes. So there an estimated 50,000 to 60,000 FTD patients in the U.S. and about 110,000 FTD patients in the EU, up to 10% of these patients carried the progranulin mutation. So I think -- so in the U.S. and EU, there could be like 15,000 to 17,000 symptomatic patients and -- but again, because the disease like symptoms occurs at the age of 50 to 60, there may be 5x more presymptomatic mutation carriers. So we think that it's very meaningful market opportunity. It's a rare disease. And again, lethal and complete unmet medical need. So we think that there is a very meaningful market for us.

What about accessing the physician network, maybe talk about the types of physicians [indiscernible] in academic centers. How do you see that unfolding?

Yes. So we are already spending a lot of time educating the scientific community, the clinical community, and it's going to be both psychiatrists and neurology, means we are working with advocacy groups. And yes, we have KOLs in all the major clinical centers. Our clinical trials are already done in like dozens of clinical centers, both in the U.S. and EU, where we have close interactions with the KOLs, but it will require educating the clinical community because not everyone knows how to diagnose FTD and what to deal -- how to deal with it.

So we are going to introduce genetic screening as part of the drug, the genetic screening is conclusive and relatively simple, and we are engaged in very extensive education and then through scientific meetings and through direct interactions with KOLs. And we think that once the community knows that there is a drug, I think the level of interest and awareness would grow significantly.

It seems like you've got enough runway in symptomatic patients, but on the genetic screening part, how do you ensure that you get proliferation of that screen to access the patients that aren't symptomatic.

Yes, even from the symptomatic patients, we want to have genetic screening because you want to make sure that the frontotemporal dementia is caused by the progranulin mutation. So again, it will be a lot of education that genetic screenings are available, easy to -- basically, it's a blood sample so the genetic screen will be easily available, and we'll have to educate the KOLs, the treating physicians and the scientific community in general that genetic screen is the way to conclusively diagnose this disease.

So could make it part of a bigger screening panel at some point?

Yes, it is -- I mean there is neurodegeneration panel, yes, that could be used here.

Moving on to 101. Can you describe the changes in PK/PD relative to aducanumab? And which make you feel 101 is more amenable for a broader population like AD.

So the unique feature of progranulin is that it appears to be a universal risk gene for neurodegeneration, whereas many risk genes are disease specific like SOD specific for ALS, alpha-Synuclein specific for Parkinson's disease, presenilin is specific for Alzheimer's disease. But in contrast progranulin, reduction in the level of progranulin appear to be associated with practically every neurodegenerative disease being tested. So 50% loss of function in progranulin leads to frontotemporal dementia, but 10% to 15% decrease in the level of progranulin are associated with Alzheimer's disease, with Parkinson's disease, with ALS, with LATE, which is another prevalent form of dementia that's typified by TDP-43.

So we think, based on this, that's elevating progranulin, either back to normal level or even super physiological level could have therapeutic benefit in many neurodegenerative diseases. And because of this hypothesis, we initiated a second clinical trial with a progranulin elevating drug, which is a drug called AL101, and this is in Alzheimer's disease, so we've just completed in April, we completed recruitment in an Alzheimer's drug.

Again, it's a placebo controlled, double-blinded Phase II with over 360 patients with our second progranulin-elevating drug and the clinical trial for the Alzheimer's study will be completed in 2026, and we have selected the second drug, this AL101 because it has a different pharmacokinetic feature. It has a half-life that's 2 to 3x longer than the 001 or latozinemab and this will enable us to either reduce dosing frequency or reducing the dose level and maybe make it more amenable to subcutaneous delivery. And we think that for the prevalent diseases like Alzheimer or Parkinson's, subcutaneous delivery could be a lot more convenient and will enable a much better patient access.

Sure maybe you should talk to Halozyme.

Yes. We have.

Unlike frontotemporal, AD patients, I believe, have relatively normal PGRN. Given that, what's the rationale supporting AL101 and increasing PGRN for having a clinical benefit in AD?

Yes. That's a great question. So the scientific rationale is twofold. Genetically, progranulin was shown to be a risk gene for Alzheimer's disease. So if you look at the 70 or 80 genes that have been identified for Alzheimer's disease, progranulin is one of them. And the risk gene is associated with 10% to 15% slowdown and decrease in the level of progranulin. So it's hard to measure like this modest reduction, but even modest reduction in progranulin leads to increased genetic risk.

And -- so there is a genetic rationale for elevating progranulin in Alzheimer's disease. The second rationale is animal model based. There are multiple studies showing that elevating progranulin to supraphysiological levels in disease models of Alzheimer's leads to therapeutic benefit. So our hypothesis that in Alzheimer's disease and eventually Parkinson's disease and ALS, elevating progranulin to a super physiological level, like two to threefold above normal level will be therapeutically beneficial.

Wonderful. Maybe you've touched on this already, but maybe just remind us of the overview of the study design in PROGRESS-AD Phase II trial. And I believe enrolments just completed? And when can we expect first data?

Yes, enrollment was completed in April of this year. It's a study with 300 patients, it's a placebo-controlled, so there is a placebo arm, and there are two doses -- two dose drug arms. It's an 18-month long study and the readout will be the CDR Sum of Box as well as like four additional clinical readouts for activity of daily living and other cognitive measures.

We are also measuring level of A-beta and tau by PET imaging, we are measuring multiple biomarkers again, A-beta 40, A-beta 42, multiple types of phospho-tau in the plasma and CSF, so it will be a fairly extensive data package that will tell us whether the drug is working and then it makes sense to continue to Phase III. The drug will be completed -- the trial will be completed in 2026. And so if you calculate from April, like 76 weeks, it will be the end of 2026, and we expect the data shortly after that.

Wonderful. Wonderful. That's on 101, but maybe to talk about the blood-brain barrier platform. We've seen several advances in the field, and could you briefly touch on Alector's proprietary BBB platform and how it's positioned within the current landscape?

Yes, absolutely. So as you know, a large molecules like proteins, enzymes and nucleic acids do not penetrate the brain well. And if you can have a shuttle that can improve brain penetration, you could have more effective drugs. So we, as several other companies have developed brain shuttle that use hitchhike on a receptor that's present in the blood-brain barrier that usually transport iron to the brain. This is the transferrin receptor. So basically, you can use the transferrin receptor as a Trojan horse to bring large molecules to the brain.

And we are using this technology to transport antibodies to the brain, to transport enzymes to the brain, and to transport nucleic acids to the brain. And we have -- with each of these drug modalities, we have a specific drug that we are advancing, in the antibody, we are developing an anti-A-beta drug, antibody drug with our blood-brain barrier shuttle that we expect, again, to reduce the side effects -- the ARIA side effects, and to increase efficacy, and we think that our unique blood-brain barrier technology will also reduce anemia compared to other technology, which is side effects associated with this technology.

For the enzymes, we are developing an engineered GCase. GCase is a lysosomal enzyme that's mutated in up to 10% of Parkinson's patients and up to 30% of Lewy body dementia patients. So there are hundreds of thousands neurodegeneration cases that are caused by loss of function mutations in this lysosomal enzyme. And again, we developed an enzyme that's a lot more stable, a lot more active than the natural enzyme and linked to the blood-brain barrier technology.

So we are able to restore enzyme deficiency in the brain of Parkinson's and eventually Lewy body dementia patients. And finally, we are also developing siRNA in conjunction with blood-brain barrier technology. And here, we are focusing on tau siRNA and alpha-synuclein siRNA. Both of these proteins are hallmarks of Alzheimer's disease and Parkinson's disease, respectively. And because a lot of the pathologies caused intracellularly, antibodies are not -- do not seem to be very effective in counteracting the misfolded protein.

And these technologies, thinking about ability to maximize penetrant, is there a trade-off between efficacy and concentration? Like how do you think about that.

Yes, this technology in general, you really have to thread the needle. It's not plug and play, means you have to really find the right configuration of the transferrin binding domain that's really optimized brain penetration but minimize adverse effects like anemia, the blood and barrier, the transferrin receptor expressed -- are expressed on the blood-brain barrier but also expressed at very high level of red blood cells. And if you bring too much of your drug to red blood cells, you can damage them. So you have to really play with the binding domain to the transferrin receptors with the affinity of the binding with the configuration of the rest of the drug to really optimize again, the safety to efficacy [indiscernible].

Just -- got a couple of minutes left, so I'll jump forward to this question, but you've recently updated guidance. Can you touch on some of the updates and remind us how much cash you have and how far that will get you.

Yes, we have over $300 million in cash. We announced that this will be sufficient to get us through the second half of 2027. And this will enable us, again, to complete our pivotal Phase III study to get readout of our Phase II study in Alzheimer's disease and to take at least two of our blood-brain barrier linked technology drugs, the anti-beta drug and the GCase drug to the clinic. So we are expected to have at least four short-term goals within our runway.

Wonderful. And with that said, is there anything that I didn't ask that you'd like to highlight or that's of particular importance.

I just want to highlight again that we have a really good mixture of late-stage program, a Phase III program for frontotemporal dementia, Phase II program for Alzheimer's disease as well as portfolio of preclinical programs that will get into the clinic in 2026 that are linked to our proprietary blood-brain barrier technology. So we are addressing both rare and major neurodegenerative diseases, frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and we are going to expand to also ALS and sporadic types of frontotemporal dementia.

Wonderful. Well, we're just perfectly on time, but thank you for your time today and thank you for coming to our conference. We really appreciate it.

Thank you. Thank you for the great questions.

Good afternoon, ladies and gentlemen, and welcome to the Alector Second Quarter and Midyear 2025 Earnings Conference Call. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to turn the call over to Katie Hogan, Senior Director of Corporate Communications and Investor Relations. Please go ahead.

Thank you, operator, and hello, everyone. Earlier this afternoon, we released our financial results for the second quarter 2025. The press release is available on our website at www.alector.com, and our 10-Q was filed with the Securities and Exchange Commission this afternoon. Joining me on the call today are Dr. Arnon Rosenthal, Co-Founder and CEO; Dr. Sara Kenkare-Mitra, President and Head of Research and Development; Dr. Giacomo Salvadore, Chief Medical Officer; Neil Berkley, Chief Business Officer and Interim Chief Financial Officer; and guest speaker, Dr. Ryan Darby, Associate Professor of Neurology and Director of the Frontotemporal Dementia Clinic at Vanderbilt University Medical Center as well as a paid consultant to Alector, who will provide clinical context on frontotemporal dementia.

After our formal remarks, we'll open the call for Q&A. I'd like to note that during this call, we'll be making a number of forward-looking statements. Please take a moment to review our slide on the webcast, which contains our forward-looking statement disclosure, and we also encourage you to review our SEC filings for more information. I would now like to turn the call over to Arnon Rosenthal, Chief Executive Officer. Arnon?

Thank you, Katie, and good afternoon, everyone. As we enter the second half of 2025, Alector is approaching an important inflection point. By mid-fourth quarter, we expect top line data from our pivotal Phase III INFRONT-3 trial of latozinemab, our most advanced clinical program. This trial represents the first rigorous test of progranulin elevating approach to treating frontotemporal dementia due to the GRN gene mutation, a fatal and rare form of dementia that strikes people decades earlier than Alzheimer's disease and currently has no approved therapy. We designed latozinemab based on clear biological and human genetic rationale to elevate progranulin levels by blocking its internalization and degradation by sortilin receptor. FTD-GRN is directly caused by progranulin deficiency and restoring it has the potential to alter the course of the disease. Our earlier studies in participants with FTD-GRN provided encouraging signals, both in biomarkers and in clinical progression.

INFRONT-3 will allow us to determine whether those findings hold up in a larger placebo-controlled double-blinded trial. Together with our partner, GSK, we are advancing [ launch readiness activities ] to help ensure we are well positioned to support the potential commercialization of latozinemab. Additionally, we are also excited about our late-stage clinical program in early Alzheimer's disease, where we are advancing AL101, our second progranulin elevating antibody, which is currently in Phase II trial. There is a strong genetic and biological rationale for the role of progranulin in Alzheimer's disease. Loss of function mutations in progranulin have been shown to increase the risk of Alzheimer's disease in humans, while overexpression of progranulin has been shown to be protective in animal models of Alzheimer's disease.

Enrollment of this Phase II trial was completed in April and trial completion is expected in 2026. AL101 shares a similar mechanism with latozinemab, but its pharmacological properties makes it suitable for more prevalent neurodegenerative diseases. In parallel, we are investing in a research and preclinical pipeline designed to fuel our future. These programs include our proprietary anti-amyloid beta antibody for Alzheimer's disease, an engineered GCase enzyme replacement therapy for Parkinson's disease and an anti-tau siRNA for Alzheimer's disease all enabled by elective brain carrier, our proprietary technology platform that enables us to deliver antibodies, proteins, enzymes and siRNA across the blood-brain barrier. This opened the door to more effective brain-directed therapies across multiple modalities.

Our late-stage clinical programs, combined with our early-stage pipeline enabled by our proprietary blood-brain barrier technology gives us the opportunity to deliver both near-term catalysts and sustained pipeline momentum. Our goal is to deliver therapies that eradicate neurodegeneration and improve patient outcomes. And in doing so, build a durable high-impact biotechnology company. Our commitment to tackling neurodegeneration drives us to engage experts who understand these diseases firsthand. It is my pleasure to introduce Dr. Ryan Darby, Associate Professor of Neurology and Director of the Frontotemporal Dementia Clinic at Vanderbilt University Medical Center.

Dr. Darby brings deep clinical expertise in frontotemporal dementia and will speak to the urgent unmet need in this disease. Dr. Darby received his undergraduate degree from Princeton University in Psychology and Neuroscience and his medical degree from Vanderbilt University. He trained in neurology at MGH and Brigham & Women Hospital as part of the Partners Neurology Harvard Medical School Program. Dr. Darby's research focuses on neurodegenerations impact on brain networks related to behavior and decision-making. His contributions to the field have been recognized with awards such as The Norman Geschwind Prize in Behavioral Neurology. Dr. Darby, thank you for joining us today. I will now turn the call over to you.

Thank you so much for the kind introduction. Today, I'll be providing an overview of frontotemporal dementia, or FTD, which is a complex and devastating group of neurodegenerative conditions that impact thousands of individuals and their families worldwide. We'll touch on its subtypes, the clinical progression, the genetic drivers like FTD-GRN and the current and future landscape of treatment and diagnosis. FTD is not a single disease, but instead a group of disorders caused by progressive neuronal cell loss in the brain's frontal and temporal lobes. This neurodegeneration leads to a broad range of symptoms, and we categorize FTD into different clinical subtypes based on those symptoms in the areas of the brain that are affected first.

First, we have the behavioral variant FTD or BVFTD, which is the most common form. It's characterized by striking changes in personality and behavior such as apathy, impulsivity and socially inappropriate behaviors. Next, there is primary progressive aphasia or PPA, which primarily impacts language. In FTD, this is further subdivided into 2 main subtypes, the semantic variants where individuals lose their understanding of word meaning and the non-fluent variant where speech becomes halting and effortful. Finally, we have FTD that presents with motor or movement-related symptoms. And this can present with overlapping conditions such as progressive supranuclear palsy, or PSP, cortical basal syndrome or CBS, and ALS FTD, which combines features of motor neuron disease with FTD.

These clinical presentations fall under the broad umbrella term frontotemporal lobar degeneration, or FTLD, which is the pathological term reflecting that underlying biology. FTD is most commonly associated with the buildup of 2 key proteins, TDP-43 and tau. However, determining which protein is involved in a living patient is extremely difficult unless there's a known genetic mutation or after death at a postmortem examination. FTD itself is more rare than Alzheimer's, but is still the most common cause of dementia in individuals under the age of 60. In the U.S., the incidence is estimated to be 15 to 22 cases per 100,000 person years, which results in a prevalence of about 50,000 to 60,000 concurrent cases in the U.S. In Europe, the number is closer to 110,000. The toll on individuals and their families in FTD is profound. FTD compared to other dementias often leads to greater functional impairments in the activities of daily living, earlier onset, frequently disrupting careers, relationships and independence.

Caregivers in FTD often report a higher burden and more painful loss or sense of personal identity and personhood compared to Alzheimer's disease, in part because these patients are presenting with emotionally disengaged symptoms and inappropriate behaviors. Approximately 30% of FTD cases have a strong family history, and we now recommend that there are 3 main autosomal dominant genetic mutations in FTD, the C9orf72 mutation, the MAPT mutation and the GRN mutation. There is at least 20 other rare mutations that are also known to be associated with FTD. Today, we're focusing on FTD-GRN, which represents about 5% to 10% of FTD cases. And this is a form that results from mutations in the GRN gene, leading to reduced levels of progranulin, a critical protein for neuronal survival and function.

Progranulin deficiency contributes to neurodegeneration through multiple potential mechanisms, including lysosomal dysfunction and inflammation. Emerging biomarkers such as neurofilament light chain, or NfL, and changes in structural brain MRI are helping us to track disease progression and onset of neuronal loss more objectively. Unfortunately, there are no FDA-approved disease-modifying treatments for FTD. Management currently is largely symptomatic and supportive, often involving behavioral strategies, speech therapy and medications targeting mood or agitation. However, there is hope on the horizon with ongoing clinical trials now targeting genetic forms of FTD, including GRN mutations, this offers an exciting opportunity to address the disease at the molecular level and develop new therapies. However, we face several key challenges.

First is the diagnostic complexity. FTD is frequently misdiagnosed or diagnosed late in the disease course. Genetic testing is not routinely performed. And even in younger patients, we often lack information about the underlying protein pathology, making it difficult to tailor interventions or enroll appropriate patients in clinical trials. Trial design is another challenge. Symptoms vary widely, not just from patient to patient, but even in the same person over time, and that can include the full range of behavioral, psychiatric, language and motor features. We need better tools to identify patients earlier in that disease course and better ways of tracking that disease over time.

Finally, there is an urgent need for disease-modifying therapies, especially in the genetic subtypes where the biology is known. Advances in biomarkers are helping move the field forward by enabling early diagnosis, better stratification and more sensitive tracking of disease progression. So in closing, FTD is a complex and deeply impactful disease, both biologically and also personally for the patients and families. With increased understanding of the genetic underpinnings like GRN mutation and the development of robust biomarkers, we're now in a position to truly develop transformative therapies. So with that, I'll turn the call over to Giacomo Salvadore, Alector's Chief Medical Officer.

Thank you, Dr. Darby, for that insightful overview of the clinical realities and urgent unmet need in frontonemporal dementia. Your perspective helps frame the importance of our work as we approach the INFRONT-3 data readout by mid-Q4. As Dr. Darby noted, FTD-GRN accounts for approximately 5% to 10% of all FTD cases. This represents about 8,000 to 17,000 cases in the U.S. and EU alone. It is striking how many people living with FTD still have no approved treatment options today, underscoring the need for continued innovation and urgency in this field. With this context in mind, I want to provide a deeper overview of the science behind our approach, the data we have generated to date and how our pivotal Phase III INFRONT-3 trial is structured.

Latozinemab is a novel investigational human monoclonal antibody developed in collaboration with GSK, and we believe it is the most advanced therapeutic candidate in development for FTD-GRN. We have evaluated latozinemab in both Phase I and Phase II clinical studies. In Phase I, the treatment was well tolerated in healthy volunteers and dose-dependent increases in plasma progranulin were observed. Our open-label Phase II INFRONT-2 study enrolled 12 participants with symptomatic FTD-GRN. Treatment with latozinemab normalized plasma and CSF progranulin levels, resulting in a two to threefold increase that was rapid and sustained over the course of treatment. We also assessed a panel of disease-relevant biomarkers, including neurofilament light chain, NfL, glial fibrillary acidic protein GFAP and markers of lysosomal function and neuroinflammation. These biomarkers moved in the direction consistent with slowing disease progression. On the clinical side, we used the CDR-NACC-FTLD-SB a validated scale for FTD that captures cognitive, functional, behavioral and language changes.

In a blinded propensity match comparison to participants from the GENFI2 natural history study, treatment with latozinemab was associated with a 48% slowing of disease progression over 12 months. These are the same clinical measures and core biomarkers being carried forward into INFRONT-3, our ongoing pivotal Phase III trial. INFRONT-3 is a 96 weeks randomized double-blind, placebo-controlled global trial evaluating latozinemab in 103 symptomatic and 16 at-risk individuals with confirmed GRN mutation. Participants received 60 milligram per kilogram of latozinemab or placebo via intravenous infusion every 4 weeks. The primary analysis will be conducted in symptomatic participants, and we plan to include at 3 participants in a sensitivity analysis. The clinical primary endpoint is the CDR-NACC-FTLD sum of boxes. Following engagement with the FDA and in line with the agency's recommendation, we and GSK have made the decision to amend the statistic analysis plan for INFRONT-3 to include plasma progranulin as a co-primary endpoint, along with the CDR-NACC-FTLD-SB.

Keep in mind that an approximate 50% reduction in progranulin is a causal factor for FTD-GRN. Additionally, we are 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. INFRONT-3 is approximately 90% powered to detect a 40% slowing of disease progression. If our key design assumptions hold, a 25% lowering is expected to be statistically significant, and we believe that will represent a meaningful clinical benefit in a disease with no approved treatment. Latozinemab has been generally well tolerated across our clinical trials with no major safety signal observed to date in either healthy volunteers or patients with FTD-GRN. As a reminder, latozinemab has received breakthrough therapy and Fast Track designation from the FDA and orphan drug designation from both the FDA and the EMA.

Following the receipt of the breakthrough therapy designation, which was granted based on our Phase II data, we had a Type B interaction with the FDA to address key elements of a potential future biologic license application. The agency indicated that the totality of the evidence, including clinical outcomes and disease relevant biomarker could support a submission for full approval pending BLA review. Additionally, we aligned on a set of fluid and imaging biomarkers that may serve as supportive efficacy data. We and GSK are preparing for potential BLA and MAA submissions in 2026, seeking full approval based on the strength of our trial design. Latozinemab represents a biomarker-driven mechanistically targeted approach to treating genetically defined FTD-GRN, a severe neurodegenerative disease with no approved therapies. We believe the strength of our clinical data, the alignment with regulators and the breadth of our clinical and biomarker package position us well as we prepare for the INFRONT-3 readout by mid-Q4.

Let me also briefly comment on AL101, our second progranulin elevating monoclonal antibody. AL101 is a distinct molecule that targets a different [indiscernible] and has a different pharmacokinetic and pharmacodynamic profile, making suitable for more prevalent neurodegenerative diseases. Importantly, as Arnon mentioned, our rationale for evaluating a progranulin elevating approach in Alzheimer's disease is grounded in human genetics. Reduced GRN expression has been implicated in Alzheimer's pathophysiology, supporting the potential of progranulin modulation in that setting. AL101 is currently being evaluated in early Alzheimer's disease with enrollment in the global Phase II PROGRESS-AD study completed in April and trial completion expected in 2026. With that, I'll now turn the call over to Sarah to share an update on our preclinical and research pipeline.

Thank you, Giacomo. As you've heard today, we are advancing our late-stage clinical programs, which have a strong scientific rationale, robust trial designs and meaningful regulatory engagement. In parallel, we are advancing a research and preclinical pipeline that reflects Alector's long-term vision. These programs are grounded in the same principles that define our clinical portfolio, a strong genetic and biological rationale and high transformational potential and a focus on serious neurodegenerative diseases with first and best-in-class therapeutic approaches. A key enabler of our preclinical and research programs is our proprietary electrobrain carrier. Delivery of sufficient drug to the brain remains a challenge for targeting neurodegenerative diseases.

Our ABC platform is a versatile blood-brain barrier transport technology that allows us to efficiently deliver a broad range of therapeutic modalities into the brain. These include antibodies, proteins, enzymes and siRNA. By selectively applying the ABC platform to drug cargoes where enhanced brain delivery can address known limitations of efficacy or safety, we believe we can expand what is possible in the treatment of neurodegenerative diseases. Our preclinical programs include a brain-penetrant anti-amyloid beta antibody for Alzheimer's disease, where a significant unmet need remains despite the approval of anti-amyloid beta antibodies. These approved antibodies have delivered plaque clearance, but only modest clinical benefit, and they are associated with side effects such as amyloid-related imaging abnormalities, or ARIA, which limit their use.

As a result, the field is increasingly focused on brain-penetrant anti-Aβ antibodies that aim to increase efficacy, reduce the incidence of ARIA, enable subcutaneous delivery and the possibility of prevention therapy. Our anti-amyloid beta antibody, ADP 037 ABCis designed to deliver on these goals. It combines a validated anti- Aβ epitope, a tailored Fc region supporting robust plaque clearance and our proprietary brain delivery ABC platform. While an emerging brain-penetrant anti-amyloid beta antibody has shown improved brain exposure and reduced incidence of ARIA in the clinic, it has introduced anemia related to transferrin receptor engagement on erythroid precursor cells as a safety concern. ADP 037 ABC also uses the transferrin receptor for transport, but it is specifically engineered to minimize anemia risk while enhancing amyloid beta clearance. With these features, we believe that ADP 037 ABC has the potential to be a best-in-class anti-amyloid candidate.

Another program I'd like to highlight is ADP 050 ABC, our engineered GCase replacement therapy. Mutations in the GBA1 gene lead to reduced activity of the lysosomal enzyme, glucocerebrosidase or GCase, and are associated with Gaucher disease, Parkinson's disease and Lewy body dementia. While enzyme replacement therapies are approved for the peripheral manifestations of Gaucher disease, these therapies do not cross the blood-brain barrier and therefore, have limited impact on neurological symptoms. With ADP 050 ABC, we aim to deliver an engineered, more stable active form of GCase to the brain, potentially restoring lysosomal function in nerve cells and ultimately countering the brain pathologies associated with Gaucher disease, Parkinson's disease and Lewy body dementia.

Beyond these 2 programs, we continue to develop a focused set of research stage candidates addressing neurodegeneration through the removal of toxic proteins, replacement of deficient proteins and restoration of immune and synaptic function. These include a brain-penetrant tau-targeting antibody, a brain-penetrant anti-tau siRNA and a reelin modulator. With that, I'll turn the call over to Neil to provide an update on our financials.

Thank you, Sarah. As summarized in our second quarter 2025 financial results, which we made available after the market closed today, we are in a strong position to deliver against our strategic objectives. We closed the quarter with $307.3 million in cash, which we continue to expect will provide runway into the second half of 2027. We have updated our 2025 financial guidance. We anticipate collaboration revenue to be between $13 million and $18 million, our total research and development guidance to be between $130 million and $140 million and our total general and administrative guidance to be between $55 million and $65 million. Our financial position enables us to stay focused on execution across our late-stage clinical, preclinical and research pipeline. We look forward to providing additional updates as we progress our work. That concludes our prepared comments for today's call. Operator, you may now open the line for questions.

[Operator Instructions] Our first question comes from the line of Tom Shrader of BTIG.

I just wanted to clarify on the statistical analysis plan, is the only change that you've added progranulin? Or is there something else there? And just give us a sense of why you added that? -- progranulin -- I mean, on average, it normalized, but did it -- does it normalize in every patient in your prior trials? I'm just trying to understand why you're doing this. And then on the ABC portfolio, is it mostly transferrin receptor based? Or are you using other receptors?

This is Giacomo Salvadore, the Chief Medical Officer. The change in our statistical analysis plan to include progranulin as a co-primary endpoint was reactive to a specific request by the FDA by statistical reviewer by the FDA who asked us to make this change to the statistical analysis plan and recognizing the important mechanistic role of progranulin. This is the only change made following a specific comment by a statistical FDA reviewer. Regarding your question about the effect on progranulin in the population of patients with FTD-GRN, we have analyzed plasma progranulin in the Phase II study, and we showed a two to threefold increase in progranulin after treatment with latozinemab. Overall, we -- based on our Phase II data as well as the longitudinal data from observational studies, we feel -- we believe that we have more than 99% power to show a statistically significant effect on progranulin.

Maybe I'll take the question on the ABC platform, Tom. So yes, while we are exploring other transporter-related transport vehicles, our lead programs that we are talking about do depend on the transferrin-mediated process.

Tom, just to add to Giacomo, we are not aware of any case where we treated patients with our drug, and we didn't see elevation of progranulin. So progranulin is consistently being elevated in treated individuals, both healthy individuals and FTD mutation carriers.

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

Yes. Following on from Thomas' first question, why did that reviewer request plasma progranulin? Like this is an antibody. I assume it's largely peripherally restricted with some minimal getting into the brain. I know tapping these patients in terms of CSF and measuring progranulin is probably problematic at this stage. But is that reviewer like are they basically agreeing that plasma progranulin with a largely peripherally restricted antibody driving that upregulation is predictive of functional benefit in a CNS disorder like frontotemporal dementia. That's the first one.

And then if Dr. Darby is still on the line, I think INFRONT-3 at its bare minimal was powered to show a 25% improvement in the slowing of cognitive decline in this trial. Just on the background of what we've seen with the uptake of anti-amyloid therapies in Alzheimer's disease showing a 27% slowing of decline. I know there's some safety concerns with that. But if it was 25%, is that still an attractive product to prescribe to this patient population?

So the FDA didn't provide detailed rationale for their input on the analysis plan and the rationale behind their suggested change and elevating progranulin coprimary endpoint. We believe that the FDA input underlines the importance of progranulin as a biologically meaningful marker in FDG-GRN. Mutation in progranulin granulin gene leads to operating insufficient and is a known case of the disease. Another point to underline is the fact that we had prior discussion with the FDA, and we disclosed those in the previous calls. And we had an agreement that elevation of progranulin could serve as confirmatory evidence in our latozinemab program.

So this change follows some previous discussion that we have disclosed before. Regarding your second comment on peripheral versus central, we -- in the Phase II study, we were able to show robust increases of progranulin two to threefold, both in the CSF as well as in plasma. Therefore, our previous data indicates a strong effect no matter what the compartment is chosen to study progranulin elevation. Yes, that is a really good correlation with our drug between the serum and the CSF, both in healthy volunteers and in patients and in both of our drugs, both in 001 and 101. So with sort of both of our drugs, the plasma progranulin appear to be a good representation of what actually will also happen in the CSF in the brain.

This is Ryan Darby. I can answer the other questions now is the right time. So in terms of that clinical benefit, I think a 25% reduction would be something that would be meaningful in a disease where we don't have any other therapeutic options. I think in the anti-amyloid infusion comparison, the issues with implementation there, I think, center around the side effects and that cost benefit profile that we're discussing with patients where some patients would opt away from that. I think in FTD with no other viable treatment options, there would be more of an interest in that would obviously depend on the other side effect profile and what that looks like. Yes. So far, sort of our drug appears to be very well tolerated. There are no sort of meaningful drug-related adverse effect. So it will be with regard to safety, a different -- appear to be a different profile than the anti- Aβ therapeutic.

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

One on AL001 from us as well. Curious how changing the SAP at this stage could affect powering on the modified CDR sum of boxes since plasma PGRN is now co-primary. And in your discussions with the FDA or and/or GSK, curious if expanded enrollment INFRONT-3 was part of your discussions at all. And given the FDA's apparent focus on PGRN levels, have you gotten a sense whether plasma PGRN could make its way on to the label as well for selection?

So to start regarding our program -- how the change in the to include progranulin as co-primary affects the power or conduct of the study, I can tell you that with having 2 co-primary endpoints, one clinical, is the CDR, FTLD sum of boxes and progranulin, we need to show statistically significance on both co-primary endpoints for the study to be positive. Having said that, these 2 co-primary endpoints are analyzed independently, meaning that the power regarding the CR sum of boxes remain unchanged. And as I said before, regarding progranulin, based on our Phase II data, we have more than 99% power to show a significant effect on elevating progranulin. The other -- sorry, can you repeat the other question?

Yes. Just given the focus of the FDA on plasma PGR, I'm curious if this could be a potential in terms of the population on the label.

Yes. We haven't had any discussions about labeling, and we will entertain discussion with regulators after we have the trial readout in mid-Q4 2025, but we didn't have any discussion about progranulin being as part of the label.

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

This is [indiscernible] on for Yaron Werber. Did the FDA mention any particular threshold that they wanted to see for progranulin? Or is that just statistical significance? And then to follow up, you mentioned the 90% power to see a 40% lowering. Was that -- are you tying that in any way to the progranulin levels? Or is that just still the sum of boxes endpoint?

Sure. The FDA didn't specify any particular threshold regarding the elevation of progranulin that they would want to see based on our trial data. They simply provided a comment that they recommended us to include progranulin change as co-primary endpoint. Then the other question was about the powering of the study power for 40% progression with latozinemab versus placebo. And this power remains unchanged after the modification. As I mentioned just now, the [ sum of boxes ] and progranulin are analyzed separately. So the initial assumption regarding CDR remain unchanged, and we -- there is no change regarding the CDR sum of boxes. And progranulin, we are 99% powered based on our Phase II data. So it doesn't -- so we don't think it's going to affect the probability of success overall. But considering the fact that we -- in order for the study to be positive, we need to show significance on both co-primary endpoints.

Yes, I'd like to add again that even if we see 25% slowdown in cognitive decline, this will be statistically significant, clinically meaningful and will most likely be approvable.

Our next question comes from the line of Sean Laaman of Morgan Stanley.

This is Mike Riad on for Sean. Congratulations on completing enrollment for progress. We have 2 questions. First one for Dr. Darby. We'd love to hear your thoughts. Assuming success restoring progranulin to normal levels in FTG progranulin, like slowing CDRS-B, would that increase your confidence in elevating progranulin above endogenous levels like being beneficial to patients with Alzheimer's?

Yes, that's an interesting question. I think that certainly showing that you can modify the level and have a benefit would help support that. I don't know if I would move you all the way to saying that super normal levels would have increased benefit, if I'm understanding that question. But certainly, restoring to normal levels shows that the intervention can do that and if it's associated with the clinical benefit that it can have an impact.

That makes sense. And then maybe just -- sorry, just a quick follow-up. What would be like your view on like other FTD subtypes?

Yes. I mean I think it would definitely make me curious of seeing what that effect could potentially be so that if this is protective, would going even above the normal levels be helpful, I think would open up that possibility or if there is a subset of patients with relatively lower -- even if it's not to the level of progranulin carriers, would that be a good treatment target and then you'd be able to show that there is something that is potentially able to do that.

That's really helpful. And then I guess my follow-up question would be for management. For INFLUNT-3, given the potential for interpatient variability on baseline progranulin level, be it by stage of disease or other factors, be it like semantic or motor disruptions, like how are you normalizing for that? Is it like the FDA requesting like within subject comparison from baseline to study end? Or is it more like an aggregate comparison between study arms?

I can take this one. So we are finalizing the SAP in close discussion with the FDA. And they -- we are going to analyze plasma progranulin change in the active arm versus placebo. So we didn't have any specific request. I can add the fact that haploid-insufficient in the granulin gene is associated with 50% reduction of progranulin levels. And this is enough to produce a disease phenotype, meaning that 50% decrease in progranulin level are almost invariably associated with frontotemporal dementia and development of the full-blown disease. Our previous data showed two, threefold elevation of plasma progranulin and we -- and also CSF data are very consistent with that, and we were able to show normalization of dose level in individuals who had baseline deficit. So Arnon, I don't know if you want to add anything, but it's -- we see a consistently low levels of progranulin in patients with FTDGR and this is a functional mutation which is associated with the disease phenotype.

Yes. Mechanistically, the mutations that cause frontotemporal dementia are full heterozygous lot of function. These are causing mutations that leads to complete ablation of the mutated protein. There's no gradation in the mutated protein. So every individual that has mutations that cause frontotemporal dementia are calling mutations that lead to haploid-insufficiency, like 50% or less of the progranulin. The promoter mutation or actually the 3 prime [ untranslated ] mutations that you referred to are a different class of mutations. These are mutations that are associated with very modest reduction in progranulin of 10% to 15%, and they are associated with other diseases like Parkinson's disease and Alzheimer's disease. And -- but they sort of they don't lead to frontotemporal dementia.

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

This is Doug MacPherson on for Graig. So thinking about the relative subjectivity of the endpoints of clinician severity score and the rating scales compared to biomarker data, is there anything that can be done or has been undertaken in orchard to try to minimize perhaps a placebo effect or to optimize for like the spread or separation between active drug and placebo?

The powering of the study take into account also the expected placebo change based on the natural history data and the natural course of the disease. Regarding biomarkers, they are unlikely to show any effect -- any placebo effect because those are objective measures, NfL as well as GFAP and volumetric MRI. There is not -- there is no placebo effect as far as we know. Regarding broadly speaking, the placebo effects on clinical outcome measures, what we know from neurodegenerative diseases is that if placebo effects are present at all, they typically tend to be manifest in the first few weeks of treatment and they tend to dissipate over time. Our trial are the INFRONT study is 96 weeks long and in a disease that show progression over time.

So we don't see the placebo effect as a particular risk for this kind of indication.

Sure. Appreciate it. And then a quick follow-up. Should we at all be concerned about ARIA for TRAEs? And if so, what would be sort of an acceptable ARIA prevalence or severity in treated patients?

Yes, you're asking about which program in particular?

I'm still on the FCD Phase III study.

So we are monitoring blinded phase 3 periodically and there is an independent monitoring committee, which oversees the safety of the drug as well, and we didn't have reports of ARIA in the study INFRONT-3. So maybe if I can add one quick thing. Typically, ARIA is observed in Alzheimer's disease and trials and it's associated with the removal of amyloid from the brain, especially from the vasculature. So in the absence of amyloid or when it is not a prominent feature of the disease I think the biological rationale for underlying the physiology is not present. Just wanted to clarify this. So the quite not expected as a feature of this treatment, and we haven't observed it so far.

Our next question comes from the line of Paul Matteis of Stifel.

This is Emily on for Paul. We were just wondering if there was a situation where you were able to hit on progranulin, but the clinical data was a bit more equivocal. How would you feel about your chances that approval in that situation?

Sure. So the study in INFRONT 3 is enrolled 103 subjects with symptomatic FTD-GRN. We collect a number of clinical measures as well as biomarkers, and we will be -- if the data support it, we will be pursuing full approval. Based on the data and given the fact that there are no approved treatments and there is a disease with a very huge burden as Dr. Darby reminded us just earlier, we will be open to have a dialogue with the regulatory authorities and the FDA based on the observed findings, which may include changes in progranulin -- we -- but again, we are meant to pursue full approval if the data supports it. And what we know from the CNS space, the FDA has recently approved drugs based on biomarker findings, if we think about the approval of tofersen in SOD1 ALS. So there are regulatory precedents, especially in CNS diseases, which are rare and with no approved treatment options. But we are pursuing full approval if the data support it.

And then just one follow-up. Were you able in that meeting with the FDA to confirm your sample -- confirm alignment on the sample size again?

Yes, sure. Thanks for the question. So we aligned on the sample size with the FDA in a meeting that we had in 2023, where we performed the blinded sample size reestimation and we observed the lower variability on the primary outcome measure, the outcome of boxes at PLD as we had in mind in our original powering assumption. So we agreed with the FDA that sample size between 90 and 100 subjects would be sufficient to show 40% [ slow disease ] progression in the active arm with latozinemab versus placebo. And we got an agreement with them on the sample size, and we enrolled 103 subjects, so over -- slightly over the number that we think is needed to show a clinical effect.

Our next question comes from the line of Pete Stavropoulos of Cantor Fitzgerald.

This is Samantha Schaeffer on the line for Pete. So a question for the team, Dr. Salvador, Dr. Darby related to INFRONT-3. We know that 16 asymptomatic patients were enrolled who will not be included in the primary analysis. Based on their baseline NfL levels, though and what we know about natural history, do you expect signs of progression and potential differences between [indiscernible] and placebo within the 96 weeks? And then I just have a follow-up question.

Sure. So as you correctly said that the primary population is patients who are symptomatic. So these 103 subjects that I just mentioned. Asymptomatic subjects, 16 of them were enrolled in the trial and will be part of sensitivity analysis. The study is ongoing and remains blinded. So we -- I cannot comment on what we expect or what we -- in terms of the ability to seize an effect in presymptomatic subjects. We will definitely look at the data and part of sensitivity analysis and possibly entertain discussions with the regulators based on the data we observed the results we observed.

Just to add to this, the recruitment of the presymptomatic patients, as you said, based on genetic mutations of frontotemporal dementia and certain threshold level of neurofilament sort of published study suggested that such patients could convert to symptomatic within the 2 years period, but we will have to see what's the actual data of the clinical trial. But that was the original expectations and the rationale for recruiting this group of presymptomatic with high level of neurofilament.

That's very helpful. And just a follow-up. We know that there's a Part 2 of the INFRANT study on -- it's an open-label extension. Can you give us a sense maybe quantitatively or qualitatively how this part of the study is progressing? Is there a high rollover rate into the OLE?

So we haven't disclosed details on how many subjects rolled over into the OLE. As a company, I can say that we are satisfied regarding the number of subjects who are actually opting in to the open-label extension, and we think that it will provide meaningful data about the persistence of the benefit in terms of clinical endpoints and biomarkers as well as what happens in subjects who switched from placebo to active treatment moving to the open-label extension. There are some very interesting and meaningful presence in the CNS space about how this open-label extension data can provide more clarity on the meaningfulness of the results from the double-blind portion of the study. So we are -- we remain interested in looking at the results. But again, the statistical -- I mean, the analysis will be focused on Part 1, which is the double-blind portion of the study, 96 weeks. So we will not focus on the open-label extension for now.

I'm showing no further questions at this time. I would now like to turn it back to Neil Berkley for closing remarks.

Thank you. Before we end the conference call, I'd like to share that Alector will be participating in a number of upcoming conferences, including the 2025 Cantor Global Healthcare Conference on September 4 in New York, the Morgan Stanley 23rd Annual Global Healthcare Conference on September 8 in New York and the H.C. Wainwright 27th Annual Global Investment Conference on September 9 in New York. Thank you again for your time and attention. We will now conclude today's call.

Thank you. This does conclude the program. You may now disconnect.

All right. Good morning, everyone, and welcome to the Goldman Sachs Annual Healthcare Conference. Delighted to be joined by the team from Alector here today. Maybe I'll kick it off. I'll let you guys introduce yourselves and maybe provide a brief overview of the company.

Sure. I'm Arnon Rosenthal. Welcome, everyone. I was -- I'm the CEO and Co-Founder of Alector. Before that, I was at Genentech for 16 years as part of the research team. Then I started Rinat Neuroscience that was acquired by Pfizer. One of the drugs that came from this company is AJOVY, the migraine drug that started the CGRP migraine therapeutics. I then started Annexon Bioscience that's a publicly traded company. And for the last 12 years, Alector is my life.

And Alector was created really with the vision and mission to really eradicate degenerative brain disorders to really make degenerative brain disorders similar to smallpox now. And in order to do this, we really created -- we built an integrated research organization that involves human genetics, protein engineering, deep understanding of cellular and an animal model for neurodegenerative disorders. We build an extensive clinical team, extensive manufacturing organization. So we are building a large integrated company that can go from ideas all the way to approval.

We currently have 2 programs in late-stage clinical development. We have a Phase III program in frontotemporal dementia, which is the second largest dementia for people under the age of 60. The readout is expected to be by the end of this year. It's a pivotal study. If it's positive, we will sort of apply for approval and hopefully, we'll proceed to commercialization.

In addition to the Phase III program, we have a Phase II program in Alzheimer's disease, and we completed recruitment for a placebo-controlled, double-blinded 18 months long trial, which is -- and we expect data sometime in 2026. In addition to the clinical programs, we have a significant portfolio of preclinical programs that target Alzheimer's disease, Parkinson's disease, Lewy body dementia, and we are integrating our programs with our blood-brain barrier shuttle to facilitate the entry of both antibodies, enzymes and nucleic acid into the brain. And sort of these preclinical programs are expected to enter the clinic next year or at least some of that.

Maybe we'll start with latozinemab in frontotemporal dementia. And you could maybe just set the stage for us on like what is frontotemporal dementia. You mentioned this earlier. What do we know about the kind of the pathogenesis of the disease? And what's the current treatment for those patients?

So frontotemporal dementia encompasses subtypes that are genetically determined. And among those, one of the most common genetic forms of frontotemporal dementia is associated mutation of the progranulin gene. These are loss of function, heterozygous loss of function mutation and roughly 5% to 10% of the cases with frontotemporal dementia are characterized by these kind of mutations.

Our drug latozinemab it binds to the sortilin, which is the major enzyme responsible for trafficking of progranulin and degradation of progranulin. And through the binding and neutralization of the sortilin receptor, our drug latozinemab is able to increase extracellular levels of progranulin by two to threefold, both in plasma and CSF.

Okay. And then I guess, what do we understand about the clinical benefit of increasing progranulin once people have disease? Is that sufficient to kind of drive clinical meaningful results?

Abnormalities and mutation of the progranulin gene are associated with 90% probability of developing frontotemporal dementia by the age of 75. So there is almost complete penetrance of the gene -- of those mutations. Frontotemporal dementia in patients with mutation of the progranulin gene is associated with a roughly 50% decrease of progranulin levels. Our drug is able to increase progranulin level two to threefold in CSF and plasma, respectively, restoring progranulin levels to normal levels. And we have seen this kind of data both in healthy volunteers as well as in patients with frontotemporal dementia in our Phase II study.

You referenced the Phase II. Maybe you could spend a bit more time on what you guys saw in that Phase II trial? And how did the results there kind of inform your Phase III design?

Yes. So the Phase II study was an open-label study. Where we enrolled different types of genetic FTD patients. Among those, we enrolled 12 patients with frontotemporal dementia and mutation of the progranulin gene. And these are the same population that we are enrolling in the Phase III study. And we saw at 12 months of treatment -- after 12 months of treatment, besides increase of progranulin that I already described, we saw changes in lysosomal markers as well as change in volumetric MRI. And we also measured CDR-NACC-FTLD sum of boxes, which is the gold standard measurement to track disease progression. And we compared the change in the CDR sum of boxes, the FTLD version to the natural progression of disease in match controls from the registry data from the GENFI study.

And we observed an improvement of disease progression by 48% using -- at 1 year using these match controls. And we also saw a positive effect compared to the natural history of the disease on other biomarkers. We saw a decrease in brain atrophy, in frontotemporal cortical atrophy as well as a decrease in ventricular enlargement compared to these natural controls.

Okay. You talked about this in that response, but there was a natural history and a match control data set. I guess how do you think about the fidelity of that natural history kind of matched population in terms of the variability across the patient population? And I guess, how much confidence do you have that, that will be kind of recapitulated in the placebo-controlled study you're doing here?

So these controls were taken from one of the 2 largest registry data set available. The name of this registry is called GENFI. And we match the historical controls to our Phase II patients according to certain baseline characteristics, such as severity of disease measured with the CDR plus NACC FTLD sum of boxes as well as matching by age gender as well as neurofilament light chain baseline level. So they were very comparable and we use propensity score matching, which is a statistical technique used very often for these kind of comparisons.

Our study is -- the population in our Phase III study is very similar to the Phase II study. And we don't -- it's a placebo-controlled trial, pivotal Phase III study, and we don't expect the placebo response to be particularly impactful because we are -- according to other studies in neurodegenerative diseases, the placebo response is not very large, and it tends to plateau after the first few weeks of treatment. And moreover, we model the magnitude placebo response in our statistical powering assumptions.

So just maybe to add 2 things. First, the FDA reviewed the Phase II open-label studies and based on the Phase II studies awarded us breakthrough therapy. So they accepted the statistical analysis and the open-label studies and sort of all the data in the open-label studies were consistent. Again, we saw normalization of multiple lysosomal and sort of neurodegenerative biomarkers.

We show a slowdown in brain tissue loss. We show slowdown in cognition by 40%. And our Phase III study is 10x larger and twice as long as the Phase II study. So we think that we have a very large margin of error even if the Phase III is not exactly as the Phase II, we still have a lot of room to...

A big cushion. There have been some other progranulin-directed agents that were discontinued. What distinguishes latozinemab in the way it works versus some of these other programs targeting the same mechanism?

So basically, what discontinued are transcriptional activators like what's called HDAC activators that were supposed to increase expression of the progranulin from the progranulin gene and they ended up not really working mechanistically, they never really worked. Nobody was really able to show in human or even in nonhuman primate that there is a meaningful elevation of progranulin. So I think that just the mechanism of action of the -- maybe one previous drug was just not working.

Now there are other therapeutic approaches. As you know, there's gene therapy, there's enzyme replacement therapy. And we are -- I mean we think that what's unique in our approach is that we are elevating the endogenous physiological progranulin in the right places and exactly in the right amount, like progranulin is a mitogen, it's a growth factor. If you elevate it more than you need, I mean there's risk of cancer basically. And if you look at other growth factors like insulin, insulin like growth factor, human growth hormone, all these factors like there is a sort of goldilock optimal level that sort of you want to elevate it. If you elevate too much, you start getting diseases.

Sure. Okay. So you've got the Phase III results coming up here soon. Maybe speak to us about the key endpoint to watch and what you're powered to detect in terms of difference between the treatment and the placebo arm.

Yes. Our Phase III study is powered to detect 40% slowing of disease progression in the active treatment arm as compared to placebo. And however, if we observe a slowing of disease progression as low as 25% according to our statistical simulations, this study would be positive.

Okay. And then what comes after kind of a positive result in this trial?

So we are well positioned to deliver meaningful clinical data by the end of 2025 in fourth quarter. And our study is adequately powered to detect a meaningful effect by the drug and the clinically meaningful -- I mean, clinically meaningful effect by the drug. And if the study is positive, we plan to proceed with this regulatory submission based on the single pivotal Phase III study.

Okay. Understood. In addition to latozinemab, you also have AL101. It's also targeting progranulin. But how is it designed to differ from the latozinemab agent?

So both AL001 and AL101 target the enzyme -- and AL101 differs from AL001 for PK as well as PK/PD characteristics, which makes it better suited to treat more common diseases such as Alzheimer's disease as well as Parkinson's disease. We -- as Arnon said, we just completed the enrollment in a really large Phase II study in April 2025, and we are expecting the results by the end of 2026. This is 76 weeks long study and the primary outcome measure is the CDR sum of boxes. And we are -- we have enrolled patients with early Alzheimer's disease.

Yes, just it's interesting that progranulin is one of the few universal risk genes for neurodegeneration, like most of the risk genes are specific for given diseases. So there's a set of risk genes for Alzheimer's disease, Parkinson's disease, ALS. And progranulin is one of the very few genes. There's maybe 1 or 2 additional genes that appear in all. It's a loss of function is a risk for frontotemporal dementia, for Alzheimer's disease, for Parkinson's disease, for late, which is another type of late-onset dementia typified with TDP-43. It's a risk for ALS. So it's a universal risk every time you see even a modest loss in the level of progranulin, even 15% to 10%, you increased risk of disease. So we are developing, again, a franchise of multiple drugs that elevate progranulin for multiple indications, and that's really what was the excitement around.

So you mentioned that the difference is on PK and PK/PD. I guess what were some of the key things you needed to optimize for as you think about setting this up for larger indications?

So we try to optimize for convenience of use. So the 101 is a 2 to 3x longer half-life compared to 001. So you can either deliver it sort of less frequently. 001 is being delivered once a month, so we can deliver 101 every 2 or 3 months or you can reduce the dose and eventually convert it to subcutaneous delivery.

Understood. And then in terms of the ongoing Alzheimer's disease study, I guess, what was the Alzheimer's disease first? And can you talk about some of the preclinical and clinical data you've reported on this agent that supported that decision?

So as Arnon just said, mutation of the progranulin genes are ubiquitous in many neurodegenerative diseases. And through our collaboration with GSK, we thought that besides frontotemporal dementia, Alzheimer's disease would be a very good indication to pursue. And especially in light of the progress made in the past decade and the identification of very valuable biomarkers that can help with decision-making and speeding up the development process. We -- in the ongoing Phase II study, we use several of those biomarkers, including fluid biomarkers that look at the markers of Alzheimer's disease such as the different p-Tau species, but we also have Amyloid PET and Tau-PET. So we decided with GSK to pursue these larger indication.

In frontotemporal dementia, you're stratifying or you're selecting for patients who have specific progranulin mutations. But in the case of Alzheimer's disease, are there biomarkers or any other features that help you select for the patients most likely to respond?

So the population enrolled in the Phase II study is very consistent with the population enrolled in other Alzheimer's disease trials. So these are patients with early AD who have evidence of amyloid pathology. We don't specifically select for patients with mutation -- any specific genetic mutation because the penetrance in Alzheimer's disease is much lower versus the frontotemporal dementia. Where, as I said, patients with progranulin mutation have more than 90% chances to develop the disease. In Alzheimer's, the link is not different. The population is, as I said, are patients with early AD with presence of amyloid pathology.

The rationale for going with all comers is that, for example, in animal models, overexpressing progranulin beyond normal level is protective in multiple Alzheimer's disease models.

Okay. So in terms of the Phase II study, what would you look to see? And maybe also this is a question sort of for how the partnership works, but what will you look to see to proceed forward with Phase III studies in this indication?

So the primary outcome measure is the CDR sum of boxes, which is the gold standard, one of the accepted clinical and functional measures to determine whether the drug is effective in Alzheimer's disease. We also collect a number of meaningful biomarkers. So overall, it's a study which is -- it's an adequate length to detect an effect is 1.5 years duration, which is according to prior data, it's enough to see where meaningful effect of drugs that's in Alzheimer's disease. So at the end of the study, we'll review all the clinical data as well as all the biomarker data and make the decisions about the next steps in the program.

Yes, again, so we are measuring PET imaging for A-beta, PET imaging for Tau, CSF and serum biomarkers, [ A-beta 40/42 ], multiple phospho-tau, neurofilament, GFAP. And it's like 5 different clinical readouts. So there's a movement in any of them that's meaningful, we will proceed.

Okay. Understood. And then how do you envision the Alzheimer's disease landscape will kind of evolve with things like new mechanisms coming to bear? Do you expect this to be used in the polypharmacy sense and sequential therapy? And how does that inform the way you think about Phase IIIs?

Yes. So the data from anti-amyloid treatments that have been approved are very encouraging, and they represent a significant milestone in the treatment of Alzheimer's disease for the medical community. However, there is still lots to be done. This treatment improves disease progression by 25% to 35% and doesn't do not -- there is room for even larger improvement. They also -- we also know that there are some patients, especially patients with more advanced disease, which do not benefit as much from anti-amyloid treatment.

Moreover, as we all know, there are significant hurdles for the implementation of those treatments in the field, which are driven by the frequency of ARIA, especially in patients who are APOE4 homozygous. So there is definitely a lot of room to improve the current treatment in Alzheimer's disease. Our drugs, drug AL101 has a different mechanism. It modulates progranulin, which above physiological levels. And we think that progranulin is a very important modulator of the immune function as well as neuronal survival. So we think that it may be as well as complementary mechanism to existing anti-amyloid treatment, which target only the amyloid plaques.

Regarding the mode of use, as you asked, sequential treatment combinations, I think these are -- the best approach will be data-driven. And as we can see from the Alzheimer's field, there are different ways of administering drugs with different mechanism of action that are being tested if we think about all the way that our treatments are combined with anti-tau treatments. So we still don't have the best answers, but what is the optimal way to combine treatment with different mechanism of action. However, we think that given the diversity of AL101, there is plenty of room for the drug to coexist with anti-amyloid treatments either in a sequential way or even as a combination treatment as our drug doesn't so far hasn't shown or other side effect profile or similar side effect profile with anti-amyloid.

Okay. And then maybe last question on this program. Just remind us the parameters around the GSK collaboration and what gets triggered with positive Phase II results?

So I mean the whole franchise is a 50-50 profit share collaboration. We received -- when the collaboration was established, we received $700 million upfront payment. It's a total of $1.5 billion milestones, which includes for 001, like first commercial sale in the U.S. is $160 million. Commercial sales in the EU is $90 million. And we have commercial leadership in the U.S., so we are the commercial lead in the U.S. For the 001, there is a similar sort of situation for 101. It's a 50-50 profit share in the U.S. and royalty, which mimic 50-50 ex U.S.

Okay. Great. Maybe we could spend some time on your pipeline. Last summer, you introduced a suite of electro brain carrier ABC candidates. Maybe you can speak to the brain carrier technology that you've developed first.

Yes. So we are developing brain carrier that should enable us to deliver drug more efficiently to the brain, and we are going after antibody drugs, enzyme drugs and nucleic acid drugs. So it's a pretty versatile technology. We are using the Trojan horse technology that sort of other people are using basically hitch hiking on either the transferrin receptor or the CD98, which is an amino acid transport. What's unique in our technology is the sort of the degree of versatility means we have a very large range of affinities to the receptors.

And the technology in general, is not plug and play. You have to really tailor the technology for the given drugs, means you have to play between efficacy and safety. Because specifically, for example, for the transferrin-based technology, means that the target-mediated adverse effects are hematologic because there is a lot of transferrin receptor on red blood cells. There's actually 100x more transferrin receptors on red blood cells compared to the blood and d endothelial cells and if you are somehow bind red blood cells and recruit the immune system to attack red blood cells, you lead to anemia and that's sort of an intrinsic problem in this technology.

So you really have to play with like the affinity, with the binding epitope for each drug to optimize the safety and efficacy. And we have, I think, unique ability to do that. We have a 1,000-fold range of affinities that we can play with. We have unique epitopes that actually may exclude simultaneous interactions with red blood cells and immune cells to increase safety. We have -- we can use multiple configurations to optimize for the different drugs.

So we have a different technology for antibodies and even this depends on the antibody like whether if you need a full effector function, if you want the antibody to recruit the immune system, you use a certain type of affinity and epitope transferrin. If you do enzymes and you don't need a full effector function, you can use a different technology with maybe higher affinity and the same for nucleic acid. So for example, if you want to remove beta amyloid with an anti-beta antibody, you need to recruit the immune system because the anti-beta antibody just tag the site, you need the excavator, you need the immune system to really dislodge. So you need to recruit the immune system. But if you recruit the immune system to A-beta plaques, you also recruit the immune system to red blood cells. So there is really a very delicate balance that I think we can really optimize better than most other technologies.

Okay. How do you think about the context where transferrin versus CD98 are the most appropriate target?

So, so far, the sort of transferrin is more validated. It's been in the clinic, both in the context of enzyme replacement therapy and in the context of antibodies and although there are cases of anemia, especially again, if you have full effect of function as in the case of traztuzumab with Roche, it sort of seem to be manageable. So transferrin, the limitations are known and they are really mainly safety associated with hematologic side effect.

With CD98, there is still less understanding of the safety profile. So we are working very extensively to really establish the safety profile of CD98. I mean there are differences like in the kinetics of entry to the brain in the cell types that express the different shuttles that may again impact brain distribution. So ultimately, it will be good to have more than one shuttle. But so far, everyone is using transferrin, it's a lot more validated.

Right. How did you think about selecting an A-beta antibody for your first ABC brain shuttle -- ABC candidate?

So yes, we are sort of aiming to really develop the best-in-class anti-A-beta antibodies with brain shuttle. So we are optimizing each of the components -- the lead program now is the traztuzumab from Roche, but their naked antibody actually was inactive like the gantenerumab, which was the precursor for traztuzumab was inactive as a naked antibody. So we are choosing epitope that is very potent as a naked antibody more similar to the Lilly antibody, donanemab.

Also, Roche saw incidence of anemia. They claim that it's manageable. But so far, patients were not treated for that long. So I think anemia is a cumulative effect. It will become worse this time. So we have a different transferrin technology, which we think will have much less anemia risk.

And compared to other technologies, like people are trying to solve the anemia problem in different ways. For example, [ AAA ] and AbbVie are inactivated. They don't -- they have an inactive effector function, and they hope that the transferrin receptor will somehow recruit immune cells. We think that this approach is less likely to fully recruit immune cells. So I think that we will have an optimized antibody that has the best epitope as a naked antibody, the best transferrin technology to minimize anemia.

The other program that you have using ABC technology has a GCase enzyme. I guess why did you select that? And sort of could you give us a high level on that molecule?

So GCase is a lysosomal enzyme that's mutated in over 10% of Parkinson's patients, it's causing like 10% of Parkinson's patients. It causes up to 30% of Lewy body dementia. It's a validated enzyme replacement modality because if complete loss of function of GCase leads to Gaucher disease and there are good enzyme replacement therapies for Gaucher disease. So it's a relatively validated enzyme replacement target. The only issue until now for Parkinson's disease and Lewy body dementia was that it didn't enter the brain. So we basically now engineered the enzyme to become significantly more stable, more active, and we integrated the blood-brain barrier shuttle. So we think it would be a good drug for Parkinson's disease and eventually Lewy body dementia.

What are the next steps for those programs in terms of getting into the clinic? And to what extent does like one program validate the technology for multiple.

Yes. So we are targeting both the A-beta and GCase to be in the clinic next year. Yes, each one of them will validate the technology. But as I mentioned, like there are actually different variations. And we are also developing siRNA to siRNA with brain shuffle, which will also have a tailored technology. So I think each of these drugs like the antibody A-beta antibody, the GCase enzymes and the Tau-siRNA will validate maybe the drug modality, but they will validate the technology in general if there is little safety issues and good brain penetration.

Okay. Maybe in our last minute, you can just talk about kind of your like strategic and overall approach to thinking about capital allocation across the early-stage portfolio versus the later-stage programs.

Yes. So we have sort of resources like our runway is through the second half of 2027. We have over $350 million. Our clinical programs are already fully funded, like our Phase III drug is fully funded. Our Phase II drug is fully funded. And we have resources to develop A-beta, GCase and Tau, sort of toward the clinic. So we think we will have -- like in the next 2 years, we will have a really good portfolio of clinical programs and earlier stages clinical program.

And maybe since I have 30 seconds, I'll ask you one more question, which is you guys have partnered a lot of your early programs. As you look to the ABC candidates, will you take a similar approach? Or do you want to wholly own those?

Our preclinical programs are currently fully owned. Yes, if there is a proposal that we can't refuse, we will explore it absolutely. But at this point, we are developing it as a fully -- we are developing the preclinical programs as fully owned.

Perfect timing. Thank you so much for joining us. Really appreciate the discussion this morning.

Thank you very much.

Thanks.