The 2025 Bank of America Healthcare Conference. Thanks for joining this session with Alector. My name is Alex Rehan. I'm a senior biotech analyst covering Alector at Bank of America.
Sara Kenkare- Mitra.
President and head of research and development at Alector. With that, Sara's 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. Oh. That sound okay? Okay, great. All right, thank you. Firstly, I just want to say that we're going to make some forward-looking statements here today. Please refer to our disclosures and our SEC filings for further details. Firstly, I just want to introduce Alector. Alector has its position to drive near and long-term value in treating brain disorders. Our therapeutic candidates are grounded in our three R 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. 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 two molecules, latazinumab and AL101, which are part of our progranulin franchise. 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. Talk briefly about our clinical programs. We have two clinical molecules, latazinumab or AL101, in frontotemporal dementia with a granulin mutation. In this program, it's currently in phase three 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 two showed encouraging results in clinical outcome measures. On the other hand, AL101, which is being studied in Alzheimer's disease, is currently in phase two. We've completed enrollment in the trial, sorry, 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 Brain Carrier, which is our blood-brain barrier technology platform. It is focused on three targets: removing Aβ, 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. Excuse me. Our Alector Brain Carrier has a number of versatile features. We have ABCs as FABs or SCFPs that bind transferrin receptors in multi-specific formats. They are optimized for effective 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. 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 non-human primates on the left, where we see up to 44% brain uptake to about 18 nanomolar in the brain. 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. 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. On the right, our reticulocyte level seven days post-injection.
Once again, we're 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. As I mentioned, we have two molecules, latazinumab and AL101. Firstly, these two programs are based on our pioneering approach to elevating progranulin levels with the potential to enhance microglia and neuronal function in treating FTD and AD. They are based on a strong genetic and biologic rationale. Mutations in granulin, which encode progranulin, are deleterious. What we know is that 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% penetrance.
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 latazinumab bind the receptor sortilin, which is critical for the degradation of progranulin. By binding and blocking the sortilin receptor, we are able to elevate progranulin levels. In patients with deficiency of progranulin, introducing latazinumab or treating with AL101 allows you to replenish these progranulin levels. We see exactly that. We first studied latazinumab in healthy volunteers. The data we show here is in INFRAN2, which is a trial where we treated 12 symptomatic subjects with FTD granulin, with latazinumab at 60 mcg q4 weeks for 49 weeks.
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. What I show here is one of those biomarkers, which is GFAP, which is a biomarker of disease activity of astrogliosis. What you see on the left is plasma concentrations, right in CSF. 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 GenFEE registry.
Based on this comparison, 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%. Past the success of INFRAN2, we've been treating patients in our pivotal phase three study, which is INFRAN3 with latazinumab. This study is a randomized double-blind placebo-controlled study, and it contains 103 symptomatic individuals and 16 at-risk FTD GRN carriers. They've been treated with latazinumab at 60 mcg or placebo for a duration of 96 weeks. We are measuring at the end of this study, the primary endpoint will be the CDR plus NAC FTLD sum of boxes, along with secondary clinical endpoints, as well as a number of biomarkers. 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 latazinumab. It has a longer half-life, and it is much better suited for larger indications. We are developing it for Alzheimer's disease. AL101 is currently in a phase two 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 latazinumab in FTD GRN. Progranulin deficiency is a risk for Alzheimer's disease, and there is sufficient data in biological disease models that suggest that it is an important factor for the course of the disease. Now, this is the design of our phase two study, which is called Progress AD. In this study, we have two 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-Aβ antibody. It's based on our own proprietary blood-brain barrier platform combined with Aβ as the target. There's been a long history with Aβ-based antibodies in the industry from the early 2000s, with a lot of failures for a while until we've had the approval of drugs like lecanamab and donanemab. 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 risks, 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 Aβ. That's wonderful because what you're seeing right now is that there's rapid Aβ clearance with these types of antibodies, there's low ARIA, but there's an additional risk of anemia. Alector is trying to develop a best-in-class Aβ-ABC paired molecule as a therapy. Our goals here are to find robust efficacy, to have a good safety profile that has low anemia, low ARIA. In addition, we want to aim for a subcu delivery for patients. In terms of the design features of our Alector anti-Aβ 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 pyroglue-3 epitope on Aβ.
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. Finally, from a safety perspective, we can fine-tune the affinity of the TFR region of 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 Aβ ABC with human iPSC microglia, you see enhanced phagocytosis of our program, of our molecule in blue. Then on the right, in vivo, in nine-month-old 5XFAD mice, you see significant reduction of Aβ plaques.
Also moving on to our second Alector fully owned portfolio molecule, which is again an ABC paired GCase enzyme replacement drug. GBA1 mutations are a major risk factor for neurodegenerative diseases. GCase is critical in the conversion of glucosyl ceramide and glucosyl sphingosine to its metabolites. When GCase is deficient, both of these substrates start accumulating. 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. 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. We've now optimized the design of an Alector ABC for GCase. 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.
It is more than tenfold active and stable than the wild-type GBA1 enzyme, which actually does not get into the brain. In addition, from a safety perspective, the Fc portion of the antibody is silent. This allows for minimal safety risk and hematologic risk. A brief data set on the left shows that our ABC molecule has over tenfold stability and activity over the naked GBA1. On the right is just an in vivo experiment in non-human primates, suggesting that we are seeing about 10-100-fold elevation in GBA1 activity in non-human primate CSF. Overall, I just want to come back to saying that Alector is focused on opportunities to drive near and long-term value.
Currently, our goals and our focus remain on our two late-stage programs, latazinumab in phase three and AL101 in phase two, and the early programs which are powered by our Alector Brain Carrier. Thanks.
All right. Flipping straight into the next session, thank you for joining this session with Caribou. My name is Alex Stranahan. I'm a senior biotech analyst at Bank of America covering Caribou. I'm pleased to be joined by Rachel Haurwitz, president and CEO of Caribou. Thanks for being here.
Thanks for having us. We really appreciate it.
We've got time for a mini fire sign here. Maybe just jumping straight into it, Rachel, maybe at a high level, walk us through sort of the current pipeline strategy and sort of the refined approach, balancing the cash and pushing assets forward.
Yeah, absolutely. Just a few weeks ago, we disclosed a number of critical decisions we've made, prioritizing the continued development of CB-010 in lymphoma and CB-011 in myeloma. In concert with this, we discontinued two phase I programs in AML and in lupus. We've also discontinued preclinical research. That allows us to really meaningfully advance these two programs, 010 and 011, to critical inflection points and to significantly increase our runway. We were able to revise guidance from funding our operating plan into the second half of 2026, all the way now into the second half of 2027. Alec, I should share, of course, these are all open-label phase I studies. We are able to learn real-time what's happening in these programs and ultimately make data-driven decisions. Doubling down on 010 in lymphoma, 011 in myeloma, this is really driven by the data.
Our enthusiasm for what we're seeing and what we've shared through these discussions is that we're seeing encouraging efficacy in both of these programs. In particular, with CB-010, seeing continued evidence that it has the potential to be on par with auto CAR-Ts. Encouraged about the future of these programs.
That's great. Obviously, that's the goal, right, is alleviate the logistical burden of auto while delivering comparable or better on the efficacy side. Maybe starting on CB-010, eagerly awaiting the updates in the second half of this year. I guess, what sort of classifies success here or would maybe dictate a go/no-go to a registrational study?
Yeah, absolutely. What are we looking for? We are looking for an allogeneic CAR-T that drives results just like the auto CAR-Ts. That's really the full picture. It's overall response rate, it's complete response rate, and it's duration of response. The data we've committed to for the readout in the back half of this year are really kind of laser-focused on this 20-patient cohort that we're enrolling, where we're intentionally applying our partial HLA matching strategy. For each of these 20 patients, we're ensuring that they receive a dose of CB-010 where they and the donor share at least four of the 12 HLA alleles. This will allow us, hopefully, to confirm what we have thus far seen retrospectively, that modest HLA matching can drive outcomes that look to be on par with auto CARs. What we've done by pushing out some of these timelines is ensuring that we have sufficient follow-up to really answer that durability question.
In particular, we've committed that for those 20 patients, a majority will at least be at the six-month mark. Some will be meaningfully beyond the six-month mark. We are really looking for an overall profile that looks and smells and sounds like an auto CAR-T.
Okay. That's great. I guess, what can you share sort of about the patient characteristics and the antler trial and how these have maybe evolved over time?
Our dose escalation work, going back to the very beginning of this program, was in third line and later patients. We enrolled 16 patients in dose escalation. Based on the very encouraging data, we went to the FDA then to seek permission to really leapfrog directly into the second line setting. They granted that. Everything since then has been exclusively in second line patients.
That has allowed us to work in our target population. That is the population that we would be making that go/no-go decision for the pivotal trial. As we first started that work, we're inherently working at sites that have ready access to auto CAR-T cell therapies. Necessarily, our trial has been kind of selecting for patients who have disease characteristics, meaning they are too sick to wait. They are part of that vast majority of patients for whom auto CAR-Ts can never be the answer. Actually, commercially, it's only 20% of patients who are getting auto CARs. There's a big chunk of that 80% who simply will never be able to wait. We know that biased initially for sicker patients in a number of ways that we can measure.
As we've continued to work and accumulate data that not only we are excited about, but physicians are excited about, and been able to leverage ex-U.S. geographies where access to auto CAR-T looks different, it's allowed us to, I'd say, modestly shift the profile of patients. We're seeing some who look a lot more like the commercial auto CAR-T patients and some for whom I think allo will always be the answer.
Okay. Is there maybe a particular threshold on our CR rate that you'd maybe put out there to help frame expectations or that you'd want to see versus other options in the second line setting?
Yeah, that's a great question. I would say a good way to kind of measure and visualize what we're looking for is to look at, say, PFS curves from the auto CARs and some of the data that we've put out historically. I imagine that is a way we will continue to visualize some of this because it captures so much of what you just asked about in one graph, right? It's really looking at the total number of patients who respond and critically how durable those responses are. Even what we've done historically is do our best to plot our data on top of some of the auto CARs to really paint that picture of similarity and outcomes. I expect we'll use proxies like that going forward as well.
Okay. Do you think PFS is still kind of the gold standard as an approvable endpoint in this setting?
It's a really great question, which probably leads me to we are actively discussing the potential trial with the FDA. Stay tuned. We expect that when we put out these data, we would be in a position to describe the pivotal study at that point in time. I will say the two approvals in the second line setting for the auto CARs, the primary endpoint was EFS.
Okay. Okay. Slightly different. Got it. Got it. Okay. The other update we'll see second half is CB-011. Maybe talk about this asset and sort of how the competitive landscape here for BCMA-directed therapies has evolved in multiple myeloma.
Yeah, the unmet need for cell therapy in myeloma is even more severe than lymphoma, right? I just said a moment ago, only 20% of lymphoma patients are getting auto CARs. Only about 10% of myeloma patients are getting auto CARs.
When we talk to myeloma physicians and ask them, "What does an allo-CAR need to look like to be relevant and appropriate for your patients?" they always point us to the bispecifics. That is the only other asset class that is readily available and broadly available off the shelf to this much larger patient population. What they are hoping to see from CB-011 or any allo-CAR would be efficacy on par with a bispecific. Let's call that at least 60-70% overall response rate. We think a baked-in expectation that the one-and-done nature of an allo-CAR is superior to a bispecific, where you are stuck on this repeat dosing for months as long as you can tolerate it with the really quite profound prolonged infection risk that comes with it.
I see. I see. That kind of leads me to my next question, which is, how would an off-the-shelf option maybe ease adoption of cell therapies? You mentioned that they're quite effective, right, or are. But 10% penetration is pretty low and probably lower than a lot of people would have expected based on the data. Do you think an off-the-shelf option is really the solution here if you can get in the ballpark?
I think it's a critical piece of the puzzle, right, because it solves for both rapid access and scale altogether, right? Even in our myeloma work, where we are doing clinical trials at the sites that have ready access to CAR-T and Abecma, we're still rapidly enrolling this study. I think it's truly demonstrative of just how significant that unmet need and therefore opportunity is.
Okay. I think you maybe already kind of touched on this, but do you think on par efficacy versus auto is required here or maybe something in between, say, a bispecific or the cell therapies could be actionable given the increased convenience?
Yeah, look, what physicians tell us is they'd love to see an allo-CAR that's at least on par with the bispecifics and that for them would be a really meaningful tool in the toolbox for their patient population. Shoot for the moon, right? Better would be better. We think that that profile alone would be incredibly attractive for this patient population.
Okay. When you think about sort of the efficacy metrics that's maybe most important, we talked about PFS maybe taking over in the LBCL setting. Is that kind of the metric here too, or is response still sort of the?
Yeah, it's a great question. I think there are a few pieces of the puzzle to highlight here. Of course, overall response rate. I think it's important to look at the fraction of patients who have a VGPR or better, certainly the fraction of patients who have a CR, restringent CR. On top of all of that is the ability to measure MRD negativity. We know that's really critical in the myeloma setting. It demonstrates critical depth of response and can be prognostic of long-term outcomes. Our update will include all of those metrics. We know MRD negativity rates are critical.
Okay. That makes sense. One question we've received from investors is just on the manufacturing and supply side of an allo program. Presumably, it should be much easier to scale for a launch, but it's also not an antibody.
There's a little bit more complexity. How do you see manufacturing sort of evolving at Caribou? And how do you sort of scale up and how quickly could that happen if you do get good data?
Yeah, I think scale is absolutely one of our advantages. For example, with CB-010, our process today results in enough cells from just one run for 200-300 doses. So it really just immediately changes the equation from the end of one auto CAR-T strategy, where instead a turn of the crank is 200-300 doses. And they have a long shelf life, right? Typically, cell therapies can sit in the freezer for years and maintain their activity. It really gives us the opportunity to completely change the game as we think about supply.
Okay. And that's kind of the scale today in-house at Caribou, right?
Actually, we develop the processes in-house. We do not do our own manufacturing. We have outsourced that. Again, we're able to leverage great expertise in CMOs who we partner with. We don't have to invest in our own brick and mortar to do this work.
Okay. Okay. That makes sense. That gives you flexibility on the capacity side as well. I guess you talked about sort of the refined pipeline strategy. Maybe talk about the updated cash runway. I think it's into the second half of 2027 now. What's sort of contemplated within this guidance and what sort of steps of de-risking does this kind of encapsulate?
Yeah, great question. Yes, our guidance is into the back half of 2027. It allows us to deliver on all the things that we've been talking about in terms of these critical data updates.
It does not contemplate, say, running the pivotal for CB-010 or doing dose expansion for CB-011. However, there's sufficient flexibility that we could do some of the setup work for a pivotal study at risk ahead of raising the capital necessary to execute on the pivotal study.
Okay. Okay. That makes sense. I guess in the last few seconds we have here, is there maybe one key focus point that you get from your investor conversations here at the conference or elsewhere that would be helpful for people to hear? Just maybe something that's misunderstood about the story or a differentiation point that you think is underappreciated.
Yeah, I think a big question that people often bring to the field, especially when they're new to the field, is, "Will allo-CAR-Ts ever result in durable outcomes for patients?" We've been doing this long enough now that for some of these patients, we know the answer is yes. For example, our very first patient dosed with CB-010, it's almost exactly four years ago, and he remains in complete response. There are an increasing number of additional patients who are past a year, past multiple years, still in complete response. I think it's really encouraging not only for our work, but for the field to demonstrate that allo-CARs can drive durable responses.
Yeah. That's the sense I hear as well. There's folks that were maybe in the initial wave of interest and are now revisiting things.
It's crazy to think that the first patient dose with CB-010 is four years out. Great to see the progress. Looking forward to the second half updates. I think we'll have to leave it there for time. Please join me in thanking Rachel for the great discussion.
Thanks, Alex. Really appreciate it.