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

2025 Bank of America Healthcare Conference. Thanks for joining this session with Alector. My name is Alec Stranahan. I'm senior biotech analyst covering Alector at Bank of America. Sara Kenkare-Mitra, President and Head of Research and Development at Alector. With that, Sara is going to run through a few slides, and I'll pass it over to you. Take it away.

Sound isn't coming from me. That noise. Sound, okay? Okay. Great. All right. Thank you. So firstly, as I just want to say that we're going to make some forward-looking statements here today. So please refer to our disclosures and our SEC filings for further details. Firstly, I just want to introduce Alector. Alector has -- is positioned to drive near- and long-term value in treating brain disorders. Our therapeutic candidates are grounded in our 3R strategy. It is a strategy to remove misfolded proteins, replace dysfunctional proteins as well as restore dysfunctional immune and neuronal cells. I'm going to touch upon our late-stage clinical programs as well as our early pipeline of preclinical assets. And we are a well-resourced team and a seasoned team. We are well resourced to get through our data readouts. Our development portfolio consists of 2 molecules, latozinemab and AL101, which are part of our progranulin franchise. And this is in collaboration with GSK in a 50-50 profit share with a co-promote. In addition, we have a wholly owned proprietary preclinical pipeline that's powered with our blood-brain barrier technology. I'll talk briefly about our clinical programs. We have 2 clinical molecules, latozinemab or AL001 in frontotemporal dementia with the granulin mutation. In this program is currently in Phase III in a pivotal study with results expected in Q4 of 2025. We have breakthrough designation, Fast Track designation and orphan drug designation. Our open-label Phase II showed encouraging results in clinical outcome measures -- on the other hand, AL101, which is being studied in Alzheimer's disease is currently in Phase II. We've completed enrollment in the trial in April of this year with a 76-week treatment period that's ongoing. The data on this are expected sometime in 2026. Our preclinical programs are focused again on the Alector carrier, which is our blood-brain barrier technology platform. And it's focused on 3 targets: removing Abeta, replacing GKs and removing Tau. Now Alector brain carrier or ABC is designed for lower dosing for improved efficacy and safety and for subcu delivery across multiple cargo types and configurations. Our Alector brain carrier has a number of versatile features. We have ABCs as Fab's or scFv's that bind transferrin receptor in multi-specific formats. They are optimized for effector function and for half-life and can be tailored to a wide range of affinities and TFR binding epitopes, facilitating optimization to multiple cargo modalities. And now we are testing it across either antibodies or enzymes or nucleic acids in multiple different versatile combinations. This is just data from one of our tool compounds that demonstrates deep brain penetration, both in nonhuman primates on the left where we see up to 40-fold brain uptake to about 18 nanomolar in the brain. And you can see it across different regions of the brain as compared to the naked antibody. On the right, the same data set is seen in rodents, where again, we see real widespread distribution of the Alector brain carrier enabled tool compound in the brain. Our ABC also shows superior serum half-life and safety and brain penetration in rodents. Again, on the left, you see the serum half-life in purple is our naked antibody and our Alector binder in pink. In the middle column is brain uptake of our tested antibodies. And on the right, our reticulocyte levels 7 days post injection. And once again, we are seeing really good features with our molecule all throughout, whether it's PK, it's brain uptake as well as safety. Moving on to our specific programs. I'm going to first talk about Alector's progranulin elevating franchise for frontotemporal dementia and Alzheimer's disease. So as I mentioned, we have 2 molecules, latozinemab and AL101. So firstly, these 2 programs are based on our pioneering approach to elevating progranulin levels with the potential to enhance microglia and neuronal function and treating FTD and AD. And they are based on a strong genetic and biologic rationale. Mutations in granulin, which encode progranulin are deleterious. Now what we know is that when -- in terms of heterozygous mutations with 50% loss of function, reduced progranulin levels to 50% of normal and frontotemporal dementia has an onset of about 58 years of age and about 90% penetrant. Now from a biological perspective, we also know that progranulin is a critical immune regulator, sort of a neuronal survival factor and also important as a lysosomal chaperone. From a mechanism perspective, AL101 and latozinemab binds the receptor sortilin, which is critical for the degradation of progranulin. By binding and blocking the sortilin receptor, we're able to elevate progranulin levels. So in patients with deficiency of progranulin, introducing latozinemab or treating with AL101 allows you to replenish these progranulin levels. And we see exactly that. We first studied latozinemab in healthy volunteers. And the data we show here is in INFRONT-2, which trial where we treated 12 symptomatic subjects with FTD granulin with latozinemab at 60 mg per kg Q 4 weeks. for 49 weeks. And what you see is both in plasma as well as in CSF, we were able to normalize, elevate progranulin levels back to what are normal levels in healthy or asymptomatic subjects. What we also saw was a change in a number of the disease biomarkers. And what I show here is one of those biomarkers, which is GFAP, which is a biomarker of disease activity of astrogliosis. And what you see in the left is plasma concentrations right in CSF. And in both instances, we can show that the biomarker of disease activity like GFAP is reduced down to what are normal levels found in asymptomatic individuals. Additionally, we also looked at cognitive decline in these subjects because it was a single-arm open-label study, we matched the data to historic controls from a registry, which is the GENFI registry. And based on this comparison, and this was done based on a propensity score matching, what we estimated was that there was a slowdown of the annual disease progression of up to 48%. Now past the success of INFRONT-2, we've been treating patients in our pivotal Phase III study, which is INFRONT-3 with Latozinemab. This study is a randomized, double-blind, placebo-controlled study, and it contains 103 symptomatic individuals and 16 at-risk FTD-GRN carriers. And they're being treated with latozinemab at 60 mg per kg or placebo and for a duration of 96 weeks. And we are measuring at the end of this study, the primary endpoint will be the CDR plus NACC FTLD sum of boxes, along with secondary clinical endpoints as well as a number of biomarkers. Now this study will be reading out, as I mentioned, in the fourth quarter of this year. AL101, on the other hand, is pharmacologically slightly different than latozinemab. It has a longer half-life, and it is much better suited for larger indications. And we are developing it for Alzheimer's disease. AL101 is currently in a Phase II study for Alzheimer's disease. As I mentioned earlier, we finished enrollment in this study in April, and we anticipate completion in 2026. The grounded basis for AL101 in Alzheimer's disease is very similar to latozinemab in FTD-GRN. Progranulin deficiency is a risk for Alzheimer's disease, and there's sufficient data in biological disease models that suggests that it's an important factor for the course of the disease. Now this is the design of our Phase II study, which is called PROGRESS-AD. In this study, we have 2 different dose levels of AL101 compared to placebo. In this study, the treatment period is 76 weeks. I'm going to skip this and move on to our wholly owned portfolio, which again is powered by Alector's brain penetrant anti-Abeta antibody. It's based on our own proprietary blood-brain barrier platform combined with Abeta as the target. There's been a long history with Abeta-based antibodies in the industry from the early 2000s with a lot of failures for a while until we have had the approval of drugs like lecanemab and donanemab. And while it's really pleasing to see that there's been real movement, particularly for patients, I think what is still a challenge is that the efficacy for these drugs has been modest. In addition, there are challenges related to ARIA and other safety risk as well as if you think about the infusion -- IV infusion that's needed for this patient, it is still quite a bit of a burden. Now the field is moving towards a much more blood-brain barrier penetrable approach to Abeta. And that's wonderful because what you're seeing right now is that there's rapid Abeta clearance with these type of antibodies, there's low ARIA, but there's an additional risk of anemia. So Alector is trying to develop a best-in-class Abeta ABC paired molecule as a therapy. And our goals here are to find robust efficacy to have a good safety profile that has low anemia, low ARIA. And in addition, we want to aim for a subcu delivery for patients. So in terms of the design features of our Alector anti-Abeta antibody that is paired with the ABC, the molecule construct has a few features that I want to point out. Firstly, really good selectivity. It's engineered in terms of high affinity and fully human antibody that selectively binds the PyroGlu3 epitope on Abeta. Secondly, really good potency. We have an active Fc region, so it can recruit the immune cells like myeloid cells to actually remove these plaques. And finally, from a safety perspective, we can fine-tune the affinity of the TFR region of the -- the TFR part of the molecule in order to reduce the hematologic toxicities. A little bit of data here showing uptake or internalization of our ABC molecule there on the left, in the green signal over a naked antibody, again, showing that our BBB transport-mediated mechanism really increases uptake into brain cells. This is in a human brain endothelial cell line. We've also shown that on the left that if you treat Alector Abeta ABC with human IPSC microglia, you see enhanced phagocytosis of our program of our molecule in blue. And then on the right, in vivo, 9-month old 5xFAD mice, you see significant reduction of Abeta plaques. Also moving on to our second Alector fully owned portfolio molecule, which is, again, an ABC paired GCase enzyme replacement drug. So GBA1 gene mutations are a major risk factor for neurodegenerative diseases and GCase is critical in the conversion of glucosylceramide and glucoslpingosine to its metabolites. When GCase is deficient, both of these substrates start accumulating. And when these substrates accumulate, they are actually toxic. In this situation, it's known that GBA1 mutations, particularly in diseases like Gaucher's disease, they're causal. And for Parkinson's disease and Lewy body dementia, they are critical. These GBA1 mutation carriers are a significant part of the population of these diseases. So we've now optimized the design of an Alector ABC for GCase. And I'll just point out a couple of features here. The GCase enzyme has been engineered with machine learning, over 1,400 mutations were engineered and screened, and it's more than tenfold active and stable than the wild-type GCase enzyme, which actually does not get into the brain. In addition, from a safety perspective, the Fc portion of the antibody is silent. So this allows for minimal safety risk and hematologic risk. And a brief data set on the left shows that our ABC molecule has over tenfold stability and activity over the naked GCase. And on the right is just an in vivo experiment in nonhuman primates, suggesting that we are seeing about 10 to 100-fold elevation in GCase activity in nonhuman primate CSF. So overall, I just want to come back to saying that Alector is focused on opportunities to drive near- and long-term value. And currently, our goals and our focus remain on our 2 late-stage programs, latozinemab in Phase III and AL101 in Phase II and the early programs, which are powered by our Alector brain carrier. Thanks.