Alector at Virtual CNS Forum: Advancing Neurodegenerative Treatments

On Tuesday, 18 March 2025, Alector Inc. (NASDAQ: ALEC) participated in the Virtual CNS Forum, presenting a strategic overview of its neurodegenerative disease treatment programs. The company showcased its robust pipeline, including promising Phase 3 trials, but also addressed challenges in meeting primary endpoints in some studies.

Key Takeaways

• Alector’s Phase 3 study for frontotemporal dementia (FTD) is fully enrolled, with results expected in Q4 2025.
• The company’s cash position exceeds $400 million, ensuring operational funding through 2026.
• Phase 2 trials for Alzheimer’s treatment (AL002) did not meet the primary endpoint, with detailed results to be shared in Vienna.
• Alector’s proprietary Blood Brain Barrier platform shows potential for significant advancements in neurodegenerative treatment delivery.

Financial Results

• Alector boasts a strong cash reserve of over $400 million.
• This financial stability supports operations beyond the Phase 3 data readout for latuzinumab in FTD patients.
• Funding is secured for upcoming clinical data events and additional program developments.

Operational Updates

• FTD Program (latuzinumab):

- Phase 3 study is fully enrolled, targeting GRM mutation patients, with data expected in Q4.

- The study aims for a 40% slowing of disease progression with 90% statistical power.

• Alzheimer’s Program (AL101):

- Phase 2 enrollment is nearing completion, focusing on early Alzheimer’s patients.

• TREN2 Program (AL002):

- The Phase 2 trial did not achieve the primary endpoint of slowing clinical progression.

- More detailed findings will be presented at the ADPD conference in Vienna.

• Blood Brain Barrier (BBB) Platform:

- A beta program for Alzheimer’s and a GCase program for Parkinson’s and Gaucher’s are advancing to clinical trials next year.

Future Outlook

• FTD Program (latuzinumab):

- Confidence in Phase 3 trial design and potential regulatory flexibility based on biomarker data.

• Alzheimer’s Program (AL101):

- Ongoing evaluation of safety and efficacy, comparing two doses to placebo.

• Blood Brain Barrier (BBB) Platform:

- Continued focus on optimizing therapeutic delivery and minimizing side effects.

Q&A Highlights

• TREN2 Program (AL002):

- Failure attributed to lack of amyloid clearance; MRI changes noted.

• FTD Program (latuzinumab):

- Emphasis on early symptomatic patients with revised statistical focus.

• Commercial Potential of FTD Treatment:

- Estimated 50,000 to 60,000 patients in the US, with double that in the EU.

• Blood Brain Barrier (BBB) Platform:

- The versatile approach allows tailored treatment delivery, potentially enhancing brain concentrations tenfold.

In conclusion, Alector’s presentation at the Virtual CNS Forum highlighted both the promise and challenges of its innovative treatment programs. For a deeper dive into the discussion, readers are encouraged to refer to the full transcript provided below.

Full transcript - Virtual CNS Forum:

Julian Pino, Associate, Stifel: Great. Thanks, everyone, for joining. My name is Julian Pino. I’m an associate on Palmer Matisse’s team here at Stifel.

I’m joined here by Mark Grasso and Gary Romano, CFO and CMO of Elector. Very excited to to have you guys, and thanks everybody for tuning in. Let’s go ahead and just dive in. I guess, first, Mark, maybe you could just provide an overview of the company, where things currently stand, and anything else that that you wanna highlight. Thanks again.

Mark Grasso, CFO, Elector: Yeah. Thanks, Julian, and thanks to Stifel for for having us again at this event. It’s great to be here. So at Elektor, you know, we’re pursuing, treatments for neurodegenerative disease and have an advanced portfolio, including, two programs, in the clinic that are progressing. The first is in a fully enrolled phase three study for, a setting called frontotemporal dementia, and this is in patients with the GRM mutation.

This this phase three study, is anticipated to, read out in q four of this year. This is a very significant unmet need. There’s no, currently approved disease modifying therapies, and and we, together with our partner GSK, are are really leading, leading the effort, to address this significant, unmet need. So, looking forward to that data later this year. We’re also progressing our second clinical program, which is, in Alzheimer’s disease.

And, this is also a sertilin inhibiting antibody, as is our lead, latuzinumab. And this program is nearing completing enrollment in a phase two study in early Alzheimer’s disease, and this is also together with our partner GSK. In addition, at Elector, we’re advancing a wholly owned portfolio of programs that we’re very excited about. And, these are utilizing, in in, many cases, our proprietary Elector Brain Carrier brain shuttle technology. And, we’re looking forward to providing additional updates around these programs, in the in the near term, including on our, proprietary and potentially best in class A beta program, which, is addressing Alzheimer’s disease, as well as a novel GCase brain shuttle replacement therapy.

This is an enzyme replacement therapy. And we’re happy to talk more about our our portfolio. We’re in a strong cash position with over $400,000,000 in cash, and that’s runway through at least twenty twenty six and a year beyond our Phase III data readout for latuzinumab in FTD GRN patients and through clinical data events for additional programs in our portfolio, including our Alzheimer’s program, in the clinic, as well as, we anticipate data for the a beta and the g case program that are advancing towards the clinic. So that’s a that’s a brief overview and, yeah, happy to go into more detail.

Julian Pino, Associate, Stifel: Yeah. Of course. No. Thanks so much. And, looking forward to to diving in, to the Sertilan programs as well as the Blood Brain Barrier platform.

And I guess just really quickly, would just be great to get, you know, any quick thoughts on the Trend two program partnered with AbbVie previously. Obviously, Alzheimer’s is extremely difficult. You know, what can you say about a l zero zero two and and, you know, what you think may have led to the failure there? And I know you said, maybe some data is going to be coming out there in the near term. So just curious if you have any thoughts?

Gary Romano, CMO, Elector: Yes. Hi, Julien. This is Gary. Thanks. And thanks for the invitation today as well.

So we shared that the INVOOC2 trial, this is the Phase two trial, the TREN2 antagonist antibody that in that study a treatment resulted in sustained target engagement and pharmacodynamic responses that indicate that we had treatment effects on microglial activation. However, we also disclosed that AL002 failed to meet the primary endpoint of slowing of Alzheimer’s clinical progression, where we measured that in a variety of ways clinically with the primary endpoint of the CDRs on the boxes and a number of other secondary clinical and functional endpoints. And also, we reported that there were no significant effects on Alzheimer’s fluid biomarkers or PET imaging demonstrating no treatment related reductions in brain amyloid levels, for example, and no other indications that there was any real treatment effects on Alzheimer’s biomarkers. As we previously reported, MRI changes that resembled amyloid related imaging abnormalities were observed in the INROVE-two study and were apparently we’re seeing more frequently and with greater severity in those who were based on APOE4 genotype with those with APOE4 homozygotes being most affected and therefore discontinued it early in the Tsinda study. And we also have disclosed that we didn’t as I said, we didn’t see any effects on amyloid PET or amyloid clearance as indicated by either PET or various fluid biomarkers.

On April 5, we do plan to present more detailed results of the INVOOC2 study during oral presentation at ADPD, that’s the International Conference on Alzheimer’s and Parkinson’s disease and that’s going to be in Vienna in a couple weeks. Got it. So we look forward to sharing more details at that time.

Julian Pino, Associate, Stifel: Excellent. Great. I think we can just go ahead and and switch gears to to AL zero zero one then. You have the ongoing phase three. I guess, really quickly, if you could just opine on you know, there’s still sort of this debate on the biological hypothesis whether, you know, SORT one blockade is is really a sort of a viable way to increase program granulin in in areas of the brain that are deficient.

I guess, can you just walk through a little bit of the rationale there, and what underscores your confidence in this mechanism?

Gary Romano, CMO, Elector: Yes, sure. So, I think the progranuline utilizes a variety of receptors, multiple receptors to signal and traffic to the lysosome including PSP, M6P, LRP1 and others. And we’ve shown and others in animal studies that blocking the sotillin receptor does not interfere with lysosomal function as you would expect if sotillin uptake of pro granulone was required by itself for normal function. And the hypothesis is that by blocking Sartillerin we can elevate progranulin, which we have done robustly showing a rapid and sustained elevation of progranulin two to three fold, which brings progranulin levels back to normal in these patients who are, who are haploinsufficient due to having a carry, a loss of function mutation in progranulin gene. But in terms of what gives us confidence, really that comes from the Phase two study of AL001 in which in addition to seeing the elevations in progranulin, we also saw changes in FTD related biomarkers in a direction that you would expect to see if treatment were slowing the progression of FTD pathophysiology.

And that includes lysosomal and inflammatory biomarkers that we know are hallmarks of the pathological changes of FTD as well as on GFAP and or glial, acidic protein, neurofilament light and, and also pre region of interest MRI, in the frontal and temporal regions in these patients. And all those biomarkers had treatment effects that were moving them as you would, as I said, as you would expect if we were slowing the progression of the disease. In addition, although it’s a small study, in addition, we did a comparison of the clinical progression in this open label study to data historical data from the Genphi natural history study and that was a blinded propensity matched analysis that showed that the latasenvab treatment slowed the progression of clinical progression in patients with FTD granulant by forty eight percent over one year of treatment. So based on all of these Phase two findings, we have confidence that we have that we are that the effect on pro granuline that we’re seeing with sort of TILIN blockade is sufficient to modify the pathophysiology and even to slow progression of the disease. And by the way, based on those Phase two findings, FDA granted us a breakthrough therapy designation for the prolativeizumab for the potential treatment of FTD granular.

Julian Pino, Associate, Stifel: Got it. It’s super helpful. And, yeah, I think I guess, like, probably the the main pushbacks, you know, some folks would would give is, you know, obviously, a small sample and, you know, comparing to natural history sort of always has its its caveats. I guess, you know, what underscores your confidence? And, I guess, as it relates to thinking about the phase three, you know, how do you sort of think about, you know, those points of critique when, thinking about the phase three design?

Gary Romano, CMO, Elector: Yeah. Well, I’m the phase three design is is is is is, you know, very, very, very similar in terms of the biomarkers and outcome measures that we saw move. So we have that study the data that we reported on that study was after one year of treatment in 10 patients. Now we have over 100 patients with early symptomatic FTD granulan that were enrolled in the study, in the Phase three study and we’re following them for two years. So I think our confidence comes from the fact that we saw this highly consistent data across various types of fluid biomarker and imaging biomarkers and the clinical outcome.

And we’re basically using the same approach with one exception, which is that we’re actually focusing this study on the early symptomatic. So it was a little bit more open ended in the Phase two study. But and we also included a small subset of patients, participants that are pre symptomatic that is they have the loss of function mutation in the granular gene and they also met criteria for an elevation of near filament light and they were enrolled. They’re not part of the primary analysis, but they will be included in sensitivity analyses.

Julian Pino, Associate, Stifel: Got it. Makes sense. Appreciate that that overview. And, you know, you talk about you, you’re enrolling a hundred patients. Can you just remind folks, was that always the case?

I know you you sort of align with regulators on, you know, a new stats plan.

Mark Grasso, CFO, Elector: Yeah. Can

Julian Pino, Associate, Stifel: you walk through that and, you know, what exactly you aligned on with FDA and how confident you are that if you were to succeed in the study that this would be sort of fileable.

Gary Romano, CMO, Elector: Yeah. Yeah. Thanks. Thanks. So, so, about a year and a half ago, I guess it was, summer of twenty three, we, we met with FDA to talk about a change in the analysis plan, not in the study itself, but in the analysis plan.

And that was based on the fact that there had been the original study was based on data from the LFTD and Genfi cohorts dating back now more than five years ago. And new data was published and came out and showed that in the this was in a publication that there was that the variability of disease progression in the cohorts in the all in these observational cohorts was less than what it had been in the earlier, you know, earlier smaller sample. And so that led us to do a sample size re estimation and saw that the variability was in fact less in the symptomatic cohort. And we had really overestimated the variability in when we came up with our sample size. And, of course, you know, the more variable progression is in the natural history of disease, you know, the more potential noise you could have and so therefore the reason you power up the study.

So, we just we realized that and we also noted that the variability both in the publication and in our sample size, RS re estimation in the pre symptomatic subjects was much higher than it was in the symptomatic, not surprisingly since they didn’t show very much change. And for that reason, we went to both FDA and EMA and proposed that we focus the primary analysis on the symptomatic subjects. And before that, the original plan was to combine the pre symptomatic and the symptomatics. So both EMA and FDA were actually quite happy with this proposal, gives you more uniform population to look at and also agreed that with the sample size reduction, we were able to reduce the sample size again because we reduced by focusing on the symptomatics we had less overall variability. And by the way, that variability doesn’t mean that there’s no treatment effect.

This is looking at aggregate data, blinded aggregate data. I want to be clear about that. So there’s still plenty of room for there to be a treatment effect between placebo and ACTIV. So that was the change that we made and that brought us that that brought our target down to between ninety and a hundred patients. And as in and we turned out to enroll a hundred and three patients with symptomatic FTD granular.

Julian Pino, Associate, Stifel: Got it. No. It makes sense. Yeah. I think I think you’re you’re anticipating sort of the next question, which is, you know, obviously, when when looking at sort of variability, I think there’s always a sense on, you know, what does it implicate for the effect size?

And, you know, could it mean that, you know, sort of these these points are just, you know, overlapping and you’re not seeing that separation? I guess, what gives you confidence that, you know, it’s it’s still viable and, you know, there’s, you know, I’m just concerned about that, basically.

Gary Romano, CMO, Elector: Yeah. I mean, the lower variability in disease progression increases our ability to determine a treatment effect, you know, with fewer patients. But as I said, you know, a blinded analysis of aggregate data, does not really provide insight into a fact size or differences between the treatment and placebo group. So and there’s really there’s still within the variability that exists, there is still plenty of room for separation, significant separation between placebo and and, and the active arm.

Julian Pino, Associate, Stifel: Mhmm. Makes sense. Great. And can you remind folks what you’re powered for here? And, you know, what were the assumptions that that fed into, you know, this sort of target effect size?

And, you know, or have there been any changes made since, you know, you changed this target enrollment size?

Gary Romano, CMO, Elector: No. You know, it’s INFRONT3 is designed was designed to provide approximately 90% power to detect a forty percent slowing of disease progression. And if our trial assumptions hold, which they there’s, you know, so far according to sample we, you know, blinded sample size estimations they have, a 25% slowing of disease progression is going to it would be expected to be statistically significant. So, we feel like we’re really well positioned here to deliver a meaningful data readout from INFRONT3. I should also I think I mentioned briefly that we had to sample this meeting with FDA based on after having getting the breakthrough designation, we had a meeting with them, FDA to discuss the variety of the biomarkers.

And we left there very encouraged. They agreed that we could that the changes in either CSF and or plasma progranulin would be stand as confirmatory evidence, which is a specific regulatory term that means that with a single positive study and confirmatory evidence could be would be potentially based on the BLA review sufficient for approval. We also discussed with them a number of biomarkers including the including NFL and GFAP and region of interest MRI and also made the case that those should be considered predictive of clinical benefit and they also agreed that based on a BLA review those biomarkers could be supportive of clinical outcomes. So we’re very encouraged by their sort of endorsement of these biomarkers and, you know, really looking forward to the readout later this year.

Julian Pino, Associate, Stifel: Got it. Yeah. That’s that’s really helpful. I guess, just on the on the biomarkers specifically, you know, we we sort of have a path established with neurofilament, you know, by by Topherson and and SaadOne. I guess, like, for example, in a scenario where if there weren’t sort of stat sig changes in PGRN, but you saw sort of changes in in NFL or the data weren’t, you know, sort of one to one totally consistent across the board.

You know, how confident would you be there? And, yeah, anything to comment on that specifically?

Gary Romano, CMO, Elector: Well, I just wanna preface it by saying, you know, we haven’t had that discussion directly yet with their agencies. I mean, that’s the kind of discussion you have when you come with data in hand, like you said, as you described. So, we haven’t discussed that specifically. But, again, I think that we can read through a bit to say that FDA has shown regulatory flexibility, they seem to endorse the biomarkers that we think are most important and have pre specified in our study. And so, we’re optimistic that they would that if as scenario something like you described, where you just missed on the primary outcome, but you have strong biomarker support that, you know, they they might exercise regulatory flexibility.

Julian Pino, Associate, Stifel: Super helpful. Great. And I think, just one last question on FTD. You know, what are your thoughts on commercial? You know, how many patients are there?

And, I guess, how frequent are these mutations and sort of this, within the broader population itself?

Mark Grasso, CFO, Elector: Yeah. We estimate there’s approximately fifty thousand to sixty thousand patients in The US with, with frontotemporal dementia and about twice that number in in The EU. But we also recognize that this is a underdiagnosed disease, that because there is no approved therapies, you know, genetic screening is not commonplace. It’s also often misdiagnosed with other forms of dementia and depression and other aspects of the disease. So those may be underestimates.

And then, it’s about five to ten percent of those patients that will have a GRN mutation. So it get you know, it’s it’s a meaningful market for a company our size.

Julian Pino, Associate, Stifel: Understood. Great. And then, switching to AL one zero one, you know, just really quickly on that program, what are the main differences between that and latuzinumab? And, you know, what underscores your confidence sort of in, you know, boosting PGRN to treat, you know, Alzheimer’s more broadly?

Gary Romano, CMO, Elector: Yes. Well, the difference is of course is an indication AL-one for those on the call, AL-one hundred and one is a study in early Alzheimer’s disease. It’s a 76 randomized double blind placebo controlled trial. It’s going to we’re going to assess the safety and efficacy of two doses of AL101 compared to placebo and the primary endpoints are more Alzheimer’s right at CDR Suboxone and the usual other clinical and functional outcome assessments and many of the same biomarkers that we used in our TRMM2 study. So very the design is actually more similar to the TRMM2 study design, which by the way even though it was negative was we were very, very pleased with the execution of that study, the clinical outcome measures as well as the biomarkers performed and showed very consistent trajectories that were highly consistent with those reported previously in the early AD population.

So, it gave us a very definitive answer on TRIM2 there, but that we weren’t looking we were hoping not to see, but at the same time very happy with the way that was executed. And that’s exactly what we’re bringing to the to this PROGRESS AD study, CRISPROF101. In terms of the rationale here, it’s different than for FTD, right. FTD, as you pointed out earlier, is a haploinsufficiency, patients have a single mutation where usually complete or close to complete loss of function and it’s a lifelong deficiency. In Alzheimer’s disease, there are some mutations that show partial much more modest changes in loss of function mutations in the granular gene that still increased the risk of Alzheimer’s disease, not to the point that it’s one hundred percent penetrance as you see in FTD, but nevertheless, even modest mutations in various analyses have showed increased risk of Alzheimer’s disease.

So the idea here is not so much that we’re normalizing progranin levels to overcome a lifelong deficiency, it’s where that we’re increasing progranin levels in hopes of protecting against it. And I should also mention that there’s animal data that has shows that increased progranulin expression and progranulin peptide does seems to protect in some Alzheimer’s mouse models. So here the hypothesis is that if a modest mutations can cause an increase in risk that increasing the levels two to threefold above, you know, above normal in this case, could be protective against, against Alzheimer’s disease.

Julian Pino, Associate, Stifel: Got it. Super helpful. And no, we’re we’re coming up close on time here, but did just wanna give you guys a a minute to talk about your Blood Brain Barrier platform. Obviously, a lot of interest in these types of, you know, technologies these days. You know, what would you like to highlight from from those programs and anything to say about, you know, the interest in in A Beta and GK specifically?

Mark Grasso, CFO, Elector: Yeah. Yeah. Very excited. And and we we do think it’s a formative time in in in the field and and for us with with these approaches. You know, we have a technology that stands out in several ways.

We have a proprietary approach. It’s a toolbox approach, which is versatile and tunable. So we’re using a transferrin receptor, CD98 heavy chain technology as well in certain cases. And this allows us, you know, to tailor first, you know, a range of cargos that could be antibodies, could be enzymes, could be nucleic acids, siRNA, etcetera. And we can have tenfold increases in brain concentrations as we’ve demonstrated in animal models.

And we do this in a very customizable way. We can customize things like affinity, valency, and we can, you know, do this in a way that allows us to to really optimize the the therapeutic window for for our programs. As mentioned earlier in the call, we’re advancing an A beta program that we believe has best in class potential. You know, this is a program that has, you know, tailored affinity to transferrin to minimize side effect issues with transferrins. You know, anemia has been seen as a concern with some other brain shuttle approaches.

And also the best in class, epitope for binding for plaque removal with the, pyroglu three a beta epitope. And then, we also are, you know, tailoring the effector portion of the antibody as well to make sure that we’re, you know, recruiting the microglia in to clear the plaque in in in an optimal way. So we’re looking forward to providing further updates on on on that program and also, updates around our our GCase program. Both of these programs are advancing to the clinic, we anticipate next year. Now the GKs, as as you may know, you know, is a naturally occurring enzyme.

It’s it’s unstable. It’s short lived. It’s difficult to manufacture. So what we’re doing is really optimizing that with a brain shuttle so you can have the first, potential neuropenetrant GKs replacement therapy. And this has a range of applications, extending from, you know, potentially, you know, GBA patients with Parkinson’s disease to Gaucher patients and, you know, a range of significant, unmet need.

So very excited about those programs as well as others that we’re advancing with our proprietary electric brain carrier, shuttle technology.

Julian Pino, Associate, Stifel: Excellent. Great. Well, I think that that about wraps up, our discussion. Thank you both so much for for joining us today. Was was great to hear these updates.

And, thank you all for for joining. Really appreciate it. Stay tuned for for the next one. Thanks, Mark and Gary.

Gary Romano, CMO, Elector: Thanks, Julian. Take

Julian Pino, Associate, Stifel: care. Bye now. Take care.

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