Alector, Inc. Price & Performance (ALEC)

I would now like to turn the call over to Arnon Rosenthal, Chief Executive Officer.

Thank you, Katie. Good afternoon, everyone. And thank you for joining Alekto's Alector first quarter and full year twenty twenty four financial results conference call. I'd like to begin by outlining our strategic direct guiding Alecto Alector.

And the opportunities that lie ahead. We are focused on discovering and developing first or best class disease modifying therapies [indiscernible] such as frontal temporal dementia, Alzheimer's disease and Parkinson's disease with high unmet medical need. Where effective medicines are urgently required. To achieve this, we continue to build an integrated biotechnology organization. That combines deep expertise in genetics, immunology and neuroscience with extensive drug discovery, protein engineering and manufacturing as well as clinical development and regulatory capability. We pursue therapies that targeted underlying mechanisms of neurodegeneration. Such as toxic misfolded proteins, deficient proteins and this function in immune, lysosomal and neuronal Our portfolio includes two first in class late stage clinical programs, developed in collaboration with GSK along with five discovery programs encompassing AN addressing both novel and more established targets. Central to our program Alector Brain Carrier or ABC. Our proprietary and versatile blood borne barrier platform. ABC aims to enhance the delivery of our protein nucleic acid therapeutics to the brain to improve efficacy and increase safety at lower doses and costs. We are advancing our wholly owned ABC based programs and expect to be in the clinic in 2026. We anticipate realized a significant portion of the company's potential in 2025.

The readout of our pivotal Phase three trial in frontotepral dementia with poganolin gene mutation is planned for later this year. Additionally, we expect to complete patient recruitment for PROGRESS AD, our Phase two trial of L-one hundred and one in early Alzheimer's disease. Beyond these initiatives, we are also advancing our preclinical pipeline which Sarah will discuss later today. Throughout this process, we remain committed to making data driven decisions that create sustainable value. With that, I'll turn the call over to Gary to discuss our goals and expectations for our clinical development programs. [indiscernible] Thank you, Arnon.

I'll begin with ladocinumab, our novel first in class progranulin elevating candidate we are developing in partnership with GSK. It is the most advanced therapeutic candidate in clinical development the treatment of frontotemporal dementia in patients with a granular mutation FTD granulins, FTD is a rare neurodegenerative disease but it is one of the most common causes of early onset dementia. Currently, there are no approved treatment options available Heterozygous loss of function mutation in the granuline gene results in 50% of normal.

And our causal for FTD with penetrance that approximates one hundred percent.

Lattacinumab is a novel investigational human monoclonal antibody designed to block and down regulate the sartilin receptor. [indiscernible] This blockade results in an increase in extracellular programming, Bladacitumab has been evaluated in Phase one and Phase two trials with ongoing evaluation in a pivotal Phase III trial for which top line data is expected by the fourth quarter. The INFRONT-two Phase II open label study evaluated treatment effects of lattosinumab in 12 subjects symptomatic FTD granulins. Effects on progranulin levels and biomarkers of lysosomal function inflammation, astrogliosis and neurodegeneration were assessed after 12 Treatment restored for granulan to normal levels in both plasma and CSF. Representing a two to threefold increase which was rapid and sustained over the treatment duration of forty nine weeks. Although the number of participants in this cohort was relatively small, all the biomarker data moved in the direction that we would expect if latocinibab slows the progression of FTD pathophysiology. To determine whether there was a treatment related slowing of disease progression, we assessed change on the CDR plus SAC FTLD somaboxes. Which is an FTD specific modification of the Clinical Dementia Rating Scale with additional modules to assess behavioral and language deficits that health authorities have confirmed will be acceptable as a primary endpoint in our pivotal Phase three trial.

We conducted a blinded comparison of disease progression rates between the latticinumab treated participants in INFRONT2 to baseline propensity match participants from the GENFI-two observational study. This analysis demonstrated clinical disease progression in latticinib treated subjects was slowed by forty eight percent over one year compared to the JENFE subjects, INFRONT-three is a pivotal Phase three randomized double blind placebo controlled trial with a treatment duration of ninety six weeks. The trial enrolled 103 symptomatic and sixteen at risk FTD Gradulone participants.

Who were randomized to receive either sixty milligrams per kilogram of latacinumab intravenously every four weeks or placebo. Importantly, in this Phase three study, we are collecting the same clinical outcome assessments and biomarkers that we assessed in the Phase two study of Vida Previously, gave alignment from the FDA and EMA to conduct the primary analysis on symptomatic participants in INFRONT three. We intend to include the at risk participants in sensitivity analyses. In February 2024, FDA granted ladizumab Breakthrough therapy designation for FTD granulin based on our INFRONT-two Phase II clinical trial data. With this designation, last year we held a Type C interaction with FDA on the potential future biologic license application for bibizinumab. The FDA indicated that it would consider the effects of lidocinumab on plasma and CSF per granulin levels as confirmatory evidence, supplementing the potential clinical effects of latazinumab, pending BLA review. We also aligned with the agency on disease relevant fluid and imaging biomarkers that may be considered as supportive evidence of clinical efficacy also subject to BLA review, Based on the FDA feedback, the strength of our trial design, we remain confident that the totality of evidence including the primary clinical endpoint and biomarkers could provide a path to potential full approval [indiscernible] In September of twenty twenty four, we presented the patient baseline characteristics for INFRONT-three at the fourteenth International Conference on Frontotemporal Dementias, or ISFTD twenty twenty four.

The baseline characteristics of symptomatic participants including age, CDR plus NAC FTLD subaboxis scores and NFL levels were representative of the broader 90% power to detect a forty percent slowing of disease progression. If our trial design assumptions hold, a twenty five percent slowing of disease progression is a expected to be statistically significant. I'd like to now turn to AL-one hundred and one, our second product candidate in our progranulin portfolio that we are developing in partnership with GSK We Why cletizumab AL-one hundred and one is a monoclonal antibody designed to block and down regulate the sartilin receptor to elevate the level of progranulin in the brain. Its distinct pharmacokinetic and pharmacodynamic properties have the potential to enable dosing regimens that may be more suitable use in the treatment of larger indications, such as Alzheimer's disease. Our Phase one study in healthy volunteers demonstrated that AL-one hundred and one was well tolerated and increased progranin levels in plasma and CSF in a dose dependent manner. The ongoing progress AD Phase trial of AL-one hundred and one, operationalized by our partner GSK is enrolling approximately two eighty two participants with early Alzheimer's disease across multiple global sites with enrollment expected to complete by mid-twenty twenty five.

The first participant was dosed just one year ago in February 2024.

ProgressAD is a seventy six week randomized double blind placebo controlled clinical trial of AL-one hundred and one designed to assess the safety and efficacy of two doses of AL-one hundred and one The primary endpoint of the study is disease progression as measured by the clinical dementia rating somaboxis. The trial also employs other clinical and functional outcome assessments and biomarkers. We look forward to sharing additional information as the trial advances, Finally, on April 5, we plan to present the results from the INVOKE two Phase two clinical trial, which evaluated the safety and efficacy of AL002, a TRM2 agonist, in individuals with early Alzheimer's disease. Results will be delivered during an oral presentation at the ADPD twenty twenty five International Conference on Alzheimer's and Parkinson's disease, taking place in Vienna, Austria.

We remain committed to advancing the understanding of Alzheimer's pathophysiology and the development of effective therapeutics for the disease.

With that, I'll now turn the call over to Sarah to provide an update on our preclinical pipeline. [indiscernible] Thank you, Gary.

We are making swift and steady progress in advancing our Alector brain carrier and our preclinical and research pipeline.

With strong momentum across several key programs, As Arnaud noted, our strategy focuses on developing product candidates that remove toxic proteins replace critical deficient proteins and restore immune and nerve cells [indiscernible] To pursue this aim, we are advancing a portfolio of programs that address both novel and established These programs leverage our deep understanding of the genetic underpinnings of neurodegenerative diseases combined with our expertise in drug discovery, and our proprietary ABC technology for blood brain barrier transport. At Elektor, Alector worked hard over several years to realize the potential of our proprietary brain carrier technology platform. Our ABC platform enables the targeted delivery of therapeutics to the brain. We believe that its versatile and tunable design enables us to optimize efficacy and safety while facilitating the efficient and well distributed transport of a wide variety of payloads. We have applied our ADC technology to multiple therapeutic cargoes, Our ABC platform targets receptors that are expressed on the blood brain barrier using receptor mediated transcytosis to enable the efficient delivery of therapeutics across the blood brain barrier and ensuring their targeted action within the brain's parangmyma. Our ABC technology is used in several of upgrade clinical programs including our candidate that replaces GKs and our candidates that target amyloid beta and tau pathology.

ADP-thirty seven ABC is our proprietary anti amyloid beta antibody paired with ABC for the treatment of Alzheimer's disease. While leveraging ABC technology, we ADP-thirty seven ABC aims to clear amyloid beta efficiently thereby reducing plaque accumulation and slowing disease progression while minimizing the risk of ARIA. It targets a validated epitopes specific to brain amyloid beta plaque Combined with an optimized antibody constant region, to enhance fibrocytosis of amyloid beta blocks. In Parkinson's disease, we are advancing ADP050ABC, a GK replacement therapy for GBA gene mutation carriers with Parkinson's disease.

In these patients, GBA mutations lead to deficient GKs activity. ADP050ABC uses an electro engineered gene gate which is proprietary and has been designed to be more stable and active. ADP050ABC aims to prevent the accumulation of toxic brain single lipids that contribute to neurodegeneration. By addressing this mechanism, our goal is to reduce cellular dysfunction and slow disease progression. We are currently selecting lead candidates for both our anti amyloid beta and GKs programs and we are on track to advance them towards IND enabling studies this year.

We are also developing two TAO targeting programs that each take a distinctive approach to tackling tau pathology for the treatment of Alzheimer's disease. One program focuses on using an anti tau antibody while the other focuses on using an anti tau siRNA. In addition, are also advancing a relin modulator designed to block tau pathology and promote synaptic function for the treatment of Alzheimer's disease. Lastly, in collaboration with the University of Luxembourg, Elektro was awarded a $1,700,000 grant from the Michael J. Fox Foundation for Parkinson's Research.

This funding will support our research on GPNMD a promising target for Parkinson's disease. Looking ahead, we plan to hold a virtual educational event in the second quarter of twenty twenty five to share additional preclinical data on our anti amyloid beta and GKs programs. As well as other advancements in our ABC platform.

With that, I'll now turn it over to Mark to provide an update on our financial results. [indiscernible] Thank you, Sarah.

As summarized in our fourth quarter and full year 2024 financial results, which we made available after the market closed today, we are in a strong cash position to deliver against our strategic objectives. We continue to focus on fiscal management and program prioritization. And as of 12/31/2024, our cash, cash equivalents and short term investments totaled $413,400,000 Now turning to our operating results. Collaboration revenue for the fourth quarter was $54,200,000 compared to $15,200,000 for the same period in 2023. Collaboration revenue for the year was 100,600,000.0 compared to $97,100,000 in 2023.

Total research and development expenses for the fourth quarter were $46,500,000 compared to $47,700,000 for the same period in 2023. Total research and development expenses for the year were $185,900,000 compared to $192,100,000 in 2023. Total general and administrative expenses for the quarter were $15,000,000 compared to $14,900,000 for the same period in 2023.

Total general and administrative expenses for the year were $59,600,000 compared to $56,700,000 in 2023. For 2025, we estimate our collaboration revenue to be between $5,000,000 and $15,000,000 Our anticipated total research and development expense And total general and administrative expenses are estimated to be between $55,000,000 and $65,000,000 We remain focused on advancing our broad and diverse portfolio as well as our electro brain care technology to treat neurodegenerative diseases. 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.

Thank you. And the first question will come from Pete Stavropoulos with Cantor Fitzgerald. Your line is now open.

Hi, good afternoon and congratulations on all the progress One question for me is, when you are thinking about the INFRONT study, treating earlier in the course of a neurodegenerative disease should result in greater clinical benefit and you see a larger separation between active arm and placebo. With that in mind, the baseline characteristics of in front, I believe twenty two percent of the patients have a CDRFPLD. Global score of zero point five forty eight percent have a score of one, thirty one, have a score of two, What gives you confidence that you enroll the correct proportion of patients for each score? That will allow you to see a clear separation between lotasinumab and placebo. And was there a cap for any of these patient populations? Yes. Hi, Tate. This is Gary. Thanks for the question. Good question. So we set out to enroll, as you said, this distribution of 0.5 to two on the global score. And this was intentional to try to target the early symptomatic [indiscernible] progressed and therefore might might not be as responsive to treatment theoretically. The other thing I just want to point out is even though that our primary analysis is focused on the symptomatic subjects that we just discussed we also collected a small cohort of patients who were [indiscernible] [indiscernible] And but had a certain met the certain threshold of NFL neuro filament light.

And we although we're not including those in the primary analysis, we will be looking at those patients with sensitivity analyses in our analysis plan. And that's at least what we're planning to do. And And I think it's not a far stretch to think that if we can find efficacy in the symptomatic subjects, that there could be a potential if we also see sensitivity analysis some benefit in the presymptomatics that patients subjects that it wouldn't be a far stretch to think that we might be able to get some type of preliminary approval pending some post marketing data. Why wait if it works as symptomatic subjects, why why should patients wait until they're impaired to start treatment? [indiscernible] Yes. When you do look at the NFL levels of those 16 patients that you enrolled at pre symptomatic And then you look at the GenFi data, Are they is there an expectation that there's actually going to be progression within this ninety six weeks Yes. Good question again. So at the time that the study started and some years ago now, as you know, based on available data, the estimate was that those patients with the NFL threshold that we used in the study would progress within the two years.

In fact, based on additional data that is quite a bit of additional data that's come out since then and analyses by the Genti and OCD group has been published, it now looks like the threshold we used [indiscernible] have would be more along somewhere between two and four years to progress to symptomatic. So So that was one of the reasons that we opted to focus our commentary analysis on the symptomatic subjects. But it's still we still expect some of these patients to have progressed and during the study. Don't forget, our study is two years along and even some of these subjects have been in for many as four years now given the long time it took to enroll Okay. All right. Thank you very much for taking our questions. Thanks Pete. And the next question will come from Alex Stranahan with Bank of America. Your line is open. Hey guys, thanks for taking our questions. Just two from us. First on AL-one hundred and one, Do you think given the share programulin targeting, there's anything to read through from in front three or is this maybe hard given the different indications And then, second question, appreciate the new color on the ABC candidate nominations.

And maybe just walk us through the preclinical optimization that's going on for these assets from here and sort of your thought process around bringing additional assets forward would be great. Thank you.

Yes. So maybe this is Gary. I'll start with that, so your first question about L-one hundred and one and hand it off to [indiscernible] I don't we don't think that there's a read through from the TREM-two trial to this trial just because the mechanisms are so very different. And in this case, we're elevating the granuline, which we believe is going to have effects on the lysosomes. And whereas the Trem-two was really a very specific approach to stimulate Trem-two signaling that would increase microheal functions in a different way. So I don't think there's much to read through there. What I would say is that in a positive way is that we feel pretty confident now that the biomarker that we used and the clinical outcome measures that we used in the TRON2 study performed very well there showing us in a very definitive way that we have a negative study. But so we are I am even more optimistic that that the biomarkers will serve us very well again this study in addition to the clinical outcomes in that we'll get a clear answer. And Alec, I heard your question right, you were asking about 101 specifically and whether one-three would be tied to the upper 101.

Okay, I missed that. Sorry. Yes. Am I correct in that, Adam?

Yeah. But that I mean, both is helpful.

My mistake.

Yes.

I thought I heard that point two. Okay, I'm sorry. Yes, I mean, I think we are looking at those I mean, I think again, there's different in the mechanism. One is in the case of the one-three study, that's the Phase three study in FDA granulin, These are patients that have a lifelong deficiency or haploins deficiency of progranulin. And our hypothesis is just by normalizing that in an early stage of the disease, we can slow or stop the disease progression. In Alzheimer's disease, it's different. These are more but the genetic show us there is that less severe mutations that cause partial loss of function appear to increase the risk of Alzheimer's disease. And so replacing it in that event could be protective against Alzheimer's. And there's also a fair amount of animal data suggesting that increasing progranil levels can be protective against Alzheimer's pathophysiology. So [indiscernible] there are a little bit more of a wink certainly than the Trem-two, but in the sense that it's all without pogranulin. But we could imagine scenarios where one might be positive and the other If one were negative, the other could still be positive.

Okay. I think your question was around ABC preclinical program. So maybe I'll just start and if you need more clarity, you can ask further. But we as we said in our press release, we are actively progressing several preclinical programs Certainly, the most advanced of those are ADT-three ABC, which is our anti amyloid beta antibody, the ABC program and the other is ADP050, which is a GK's replacement therapy for Parkinson's disease. These programs are more advanced and our goal is to to get to an IND submission and to be in the clinic in 2026. Besides that, we are also applying our ABC technology to to target tau and we're taking two different approaches there. One is an antibody approach, the other is with a tau siRNA. These are not as further along as the two programs I mentioned.

We also have a relin modulator that is designed to block tau pathology and promote synaptic [indiscernible] in Alzheimer's disease And suddenly, at this moment, I mean, if you have any other questions around this, I'm happy to answer.

That's very helpful. Thank you for the color.

And our next question will come from Paul Matteis with Stifel. Your line is now open.

Hi, this is Emily on for Paul. Just to kind of like ask a little bit more about your ABC platform. Could you maybe highlight some of the key differences with your Blood Brain Barrier platform with others such as like Denali or Roche efforts? And then also just a bit more specifically, on ADP-thirty seven and fifty, could you maybe talk a little bit more about the rationale of Alector those as your first two targets think, yes.

Yes.

I can take that. Maybe Arnaud, you can add. So I think firstly, to get to your question about our Alector ABC technology, I think it stands out in several ways. I would firstly say that our toolbox approach is versatile and tunable. And as you know with ABCs, you're trying to maximize efficacy while minimizing the potential of of safety of tolerability. And I think our technology provides because it provides for that very well because of that sort of It's not as rigid. We can fine tune both both in terms of the affinities but also in terms of being able to match the right type of fragments with the right type of cargo. So overall, that gives us a very versatile very tunable and very adaptable platform that we can apply depending on whether it's an antibody, a protein, whether you need an Fc or you don't need an Fc, etcetera.

Now coming to our two different programs, 80 037ABC, which is RAB amyloid beta technology. I We believe that firstly, it targets a validated epitope, which is Pyroglue III A beta epitope, which is which with our brain penetrant A, B, C, We also have a fully active FC. Which allow which is essential for the fibrocytosis of amyloid beta plaque. And we are also sort of configuring the affinity to TFR where we've been able to fine tune it to allow us to get sort of the most optimal half life, minimal safety as well as maximal brain penetration. Now certainly, this is all preclinical, but we believe that the combination of all of this allows AB ADP-thirty seven ABC. To have the potential to be a best in class molecule in the future. Now ADP050, ABC, which is our GK's ABC program, in targeting Parkinson's disease. Again, we are developing that this is our natural GK is a very unstable and short lived molecule. We've engineered a much more stable and active GKase enzyme through mutagenesis, which also has a minimal potential to be immunogenic. NADP050 again, compared with our ABC technology, really could enable brain penetration and the potential for for treatment of Parkinson's disease.

Great. Thank you guys so much.

The next question will come from Tom Schreiter with BTIG.

Your line is open.

Good afternoon. Thanks for taking the question. More on the shuttle, I'm afraid. Can you talk a little bit about your decision to use siRNA versus ASOs? I think almost everyone else is on the ASO side. And specifically, are there good preclinical models for some of the problems that ASOs can run into like inflammation and protein buildup When will you know if that's a differentiated approach? And maybe any thoughts you have about why you took this approach?

It seems that if the field is moving to SIR and I from a S [indiscernible] it seems that this SIRNA has more a better on target activity, so the fewer side effects better stability, But yes, we are testing it now and yes, we No, in the next six months or so, how good it is. If you look at the literature, if you compare side by side the efficacy of ASR versus SIRNA, for example, against tau means that they'll are indications that SRMA is more potent in sort of blocking the target. So it seems that this are some efficacy advantage as well as safety advantages. [indiscernible] but you're right, this is just an evolving field and we which of the two nucleic acid technologies is better? A quick follow-up. Is this Is this do you see this as a good place for M and A and some sort of another big deal Or do most companies have the technology they want? That something we should be looking for as you out licensing some piece of your technology for some non dilutive funding?

Sort of blood and barrier shuttle is still a technology that multiple companies are seeking. Means The activity sort of few companies with mature blood and biotech most of the companies with good technologies are So they're either engaged already or are going to be Quite expensive. So I think that conceptually there is a lot of means we see a lot of in our interest and there is a lot of interest in our technology And again, because it conceptually could be utilized for antibody therapeutics, enzymethylplatin therapy, nucleic acid therapy, it could improve Sort of the convenience of delivery from intravenous to subcutaneous in the case of Alzheimer's disease, it can sort of reduce or possibly eliminate aria like and first effect. So I think there is a lot of interest in the technology and I think that even though the the technology is conceptually simple like to really optimize it and really thread this needle between efficacy and safety is not so easy. And I think there are actually only two or three companies that have the mature technology. So there is still I think, a lot of demand for the technology.

Great. Thank you for the color. Thanks, Tom.

The next question comes from Yaron Werber with TD Cohen. Your line is open.

Great. Thanks for taking my question. I had a question maybe on infant three. As you're looking at the primary endpoint, in symptomatic patients, can you give us a sense just remind us how it's powered And just remind us also the data that we're going to see by year end, do you think that's going to be the fully mature data or are you going continue to follow-up at that point onwards? Thank you.

Yes. Thanks, Ron. Good questions. So the study is powered for approximately ninety percent we have about 90% power to detect a 40% slowing of disease progression And if our study design assumptions hold, with regard to proportionality and dropouts and stuff, which we expect. If we observe a 25% slowing of disease progression, at the end of the study, we expect that that will be a positive P value. So So I hope that answers your question about the power. The second part of your question data together. Yes, I'm sorry, Greg. Yes, so this will include this will be all of the data. It will be two years of data on all participants ninety six weeks data on all participants, [indiscernible] data from a long term extension that we'll also be looking at, which as I said I mentioned earlier, we've had patients now in the long term extension for as long as four years, up to four years. And also supporting biomarkers as well. Yes. So in addition to the primary endpoint, remind you that we had a a meeting with FDA middle of last year under our breaking designation status, where we discussed a number of biomarkers.

And it was very encouraging. They Agreed that we came to agreement that we could use addition to the primary endpoints, we can also lean into the changes or treatment related changes in progranium levels, both in CSF and [indiscernible] will be considered as confirmatory evidence And we also discussed a number of fluid and imaging biomarkers that we felt we've made a case that should be predictive of clinical benefit and they also agreed that those biomarkers would be looked at as potentially supportive of clinical data. So I think kind of wrapping that all up, we're we're feeling optimistic that FDA is going to look at the totality of the data. And both clinical outcomes and biomarkers. And that in this rare, very rare disease, where there's no other treatments, this gives us a good chance. We are planning for a full approval based first off the primary endpoint. Is a CDR. But But if for some reason unexpectedly the primary endpoint disappoints, I think we're going to have a lot of other potentially supportive data that could be give us a backup plan? Thanks, Jarrod.

And the next question will come from Sarah Schramm with William Blair. Your line is open.

Thanks guys. Thanks for taking the question. So going back a little bit to the preclinical program, can you just remind us specifically how that paraglutamate A beta epitope that you're targeting with 37 differs from both the approved A beta antibodies as well as some of the other ones in development, like tretinumab, which does also use a brain cell technology. Kind of how those different epitopes might lead to differentiation And could you also just remind us if that if three seventy uses a TFR or a CD98 mediated brain shuttle system?

Yes. So firstly, I mean, if let's go to the trontenumab molecule, targets the N terminal region of amyloid beta. Versus our program ADP-thirty seven, targets the pytoglue, three A beta epitope. Which actually is similar to the epitope in dolatumumab and remturnercept. And And I think the second part of your question could you repeat the second part of your question?

Sorry, Sarah?

Yes. Sure. So like how might the different epitopes lead to differentiation in terms of targeting potentially different plaques [indiscernible] Yes. I mean, I think the way we see it is that because we're targeting the PyroGlut III EBITDA epidurum, which is a validated [indiscernible] been demonstrated as a naked antibody to be effective. And so that's wonderful. As you know, the trontenumab molecule is based is a shuttle enabled molecule, the naked molecule gantinibab was not effective in the Clin A. And so I think that bodes really well to using a pyroglutide A beta epitope in our ADC construct And then in addition, as I said, we have a fully active SC and more importantly, we fine tuned our affinity for TFR. I think one of your questions was, are we using TFR NVR? For this molecule? We have configured the affinity to TFR to optimize it to have sort of minimal safety [indiscernible] optimal half life and rate penetration.

Got it. Very helpful. Thank you. Thanks, Sarah. And the next question comes from Sam Lee with Mizuho. Mizuho.

Hi, this is actually for Greg Sivanovitch. Thanks for taking our questions.

A couple on our end. For INFRONT-three, can you please remind us how you've enriched for patients more generally optimize the trial design in order to give you the best chance of [indiscernible] and also in FTD knowing that there's several programs in clinical development can you compare and contrast your approach versus the competitive programs in why you think latumumab may offer an optimal therapeutic option when compared to the other programs? Thank you so much.

Yes, thanks. I'm going to have to ask you to the first part of the question because there's a lot of background noise coming over with you. So I'm sorry about that.

Sure. Just repeating the for the first question. For Infront III, can you just remind us how you've enriched for patients and more generally like optimize the trial design to get the best chance of success to show efficacy? And then the second question with regard to just the competitive landscape for FTD, like knowing that there's several programs clinical development, can you just remind us of like the differentiating factors of Lata rutumab compare contrast the approach and why perhaps it might offer a optimal therapeutic option.

Yes. Thanks.

So Luis, thank you for that. So So this was a these FTD granulome patients while they're out there because of under diagnosis in general and also when we started this, there wasn't a lot of genetic testing. They're difficult to find. I mean, in terms of enriching, we just we really just looked with where the patients were. There were There are pockets of patients in different countries in Italy and Portugal, etcetera.

And other whether it's founder effects We went there, we built relationships with the sites and we were able to enroll, as I said, eventually over 103 symptomatic subjects In terms of the trial design, we really never the trial design is not really the trial execution has not changed. This trial started, the plan was somewhat optimistically to analyze both the symptomatic and and the presymptomatic in the same at the same time. We found that as I mentioned earlier that with more data being collected in the in the observational studies, Genphew and all FPD, we learned a few things over the time that we were enrolling in the study. One is that there was a greater variability of progression in the presymptomatic because they don't progress very quickly. And for that reason, was one of the reasons we decided to focus the primary analysis on the symptomatic subjects that we described. And that was reviewed with FDA and AMA and they were both very pleased that we were doing that. As I mentioned earlier, we'll also look still look at those presymptomatics in a sensitivity analysis.

In terms of how does our approach differentiate from others? What we do is bring for granted our mechanism by blocking sartilimin receptor increases the granular levels back to normal range. And we've shown in our Phase two study that this if you do that, that you see normalization of the number of biomarkers or always both inflammatory biomarkers biomarkers of lysosomal function, We saw a normalization of PFAP. We saw a slowing of NFL accumulation. And we also saw changes on imaging on volumetric MRI. So So and beyond that, we did a a density matched comparison of the subjects in our Phase one study to [indiscernible] patients from the Gensi study and that showed slowing of disease progression by forty eight percent. So we think we for all those reasons, we believe that this is having an effect on the on the pathophysiology I can't in terms of the other approaches, whether it's a gene therapy or delivering the protein directly, I think it's too soon to say. I mean, it may be that there's always the potential. Progrenulin is a very ubiquitous protein with many functions and we get a little nervous when we think about increasing the granule levels well above normal. [indiscernible] approach normalizes them.

So I think we'll know with time whether more is better or whether some of these other approaches are more or less Alector, but they're pretty far behind. I mean, we're we're months away from a readout on our Phase three study and We're quite optimistic.

That's really helpful color. Thank you so much.

I show no further questions at this time. I would now like to turn the call back over to Mark for closing remarks. Thank you, operator. Before we end the conference call, I'd like to share that Elektra will be participating in a number of upcoming conferences including TD Cowen's forty fifth Annual Healthcare Conference next week, March 4 in Boston, we'll be there. LYRX twenty twenty five Global Biopharma Conference the following week will be there March 11 in Miami. And we're also looking forward to Stifel's twenty twenty twenty twenty five virtual CNS Forum on March 18. You again for your time and attention and we will now Thank you. This does conclude today's conference call.

Thank you for participating.

Goodbye. [indiscernible]