Alector Q4 2024 Earnings Call Transcript

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Provided by Quartr
February 26, 2025

There are 11 speakers on the call.

Operator

Good afternoon, ladies and gentlemen, and welcome to Elektor Fourth Quarter and Full Year twenty twenty four Earnings Conference Call. At this time, all participants are in a listen only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during this session, you would need to press 11 on your telephone. You will then hear an As a reminder, this conference is being recorded.

Operator

I would now like to turn the call over to Katie Hogan, Senior Director of Corporate Communications and Investor Relations. Please go ahead.

Speaker 1

Thank you, operator, and hello, everyone. Earlier this afternoon, we released our financial results for the fourth quarter and full year '20 '20 '4. The press release is available on our website at www.electro.com and our 10 K was filed with the Securities and Exchange Commission this afternoon. Joining me on the call today are Doctor. Arnon Rosenthal, Co Founder and CEO Doctor.

Speaker 1

Sarah Kankari Mitra, President and Head of Research and Development Doctor. Gary Romano, Chief Medical Officer and Doctor. Mark Grasso, Chief Financial Officer. After our formal remarks, we'll open the call for Q and A. I'd like to note that during this call, we'll be making a number of forward looking statements.

Speaker 1

Please take a moment to review our slide on the webcast, which contains our forward looking statement disclosure. We also encourage you to review our SEC filings for more information. I would now like to turn the call over to Arnon Rosenthal, Chief Executive Officer. Arnon?

Speaker 2

Thank you, Katie. Good afternoon, everyone, and thank you for joining Electro's Fourth Quarter and Full Year twenty twenty four Financial Results Conference Call. I'd like to begin by outriding our strategic direction guiding Electro forward and the opportunities that lie ahead. We are focused on discovering and developing first or best in class disease modifying therapies for neurodegenerative disorders such as frontotemporal dementia, Alzheimer's disease and Parkinson's disease with high unmet medical needs, 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.

Speaker 2

We pursue therapies that targeted underlying mechanisms of neurodegeneration such as toxic misfolded proteins, deficient proteins and dysfunction in immune lysosomal and neuronal systems. Our portfolio includes two first in class late stage clinical program developed in collaboration with GSK along with five discovery programs encompassing antibodies, enzymes and nucleic acids addressing both novel and more established targets. Central to our program is Electro Brain Carrier or ABC, our proprietary and versatile blood band barrier platform. ABC aims to enhance the delivery of our protein and 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.

Speaker 2

We anticipate realizing a significant portion of the company's potential in 2025. The readout of our pivotal Phase three trial in frontotepal dementia with pro bono ring gene mutation is planned for later this year. Additionally, we expect to complete patient recruitment for FORBES AD, our Phase two trial of AL101 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.

Speaker 2

With that, I'll turn the call over to Gary to discuss our goals and expectations for our clinical development programs. Gary?

Speaker 3

Thank you, Arnon. I'll begin with latasumumab, our novel first in class for granuline elevating candidate, which we are developing in partnership with GSK. It is the most advanced therapeutic candidate in clinical development for the treatment of frontotemporal dementia in patients with a granulin mutation or FTD granulin. 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 for patients with FTD.

Speaker 3

Heterozygous loss of function mutations in the granulant gene results in haploinsufficiency of progranulant, reducing CNS levels to 50% of normal and are causal for FTD with penetrance that approximates 100%. Latazinumab is a novel investigational human monoclonal antibody designed to block and down regulate the sartellin receptor, which is one of several receptors that take up progranulin from the extracellular space. This blockade results in an increase in extracellular progranulin. Lidazinumab has been evaluated in Phase I and Phase II trials with ongoing evaluation in a pivotal Phase III trial for which top line data is expected by the fourth quarter. The INFRONT2 Phase two open label study evaluated treatment effects of latasinumab in 12 subjects with symptomatic FTD granular.

Speaker 3

Effects on progranulin levels and biomarkers of lysosomal function, inflammation, astragliosis and neurodegeneration were assessed after twelve months of treatment. Treatment restored pro granuline 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 a direction that we would expect if latasinumab 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 MAC FTLD sum of boxes, 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 III trial. We conducted a blinded comparison of disease progression rates between the latuzinumab treated participants in INFRONT2 to baseline propensity match participants from the GENCV2 observational study.

Speaker 3

This analysis demonstrated that clinical disease progression in elatedizumab treated subjects was slowed by forty eight percent over one year compared to the Genphi subjects. INFRONT3 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 16 at risk FTD granulant participants who were randomized to receive either sixty milligrams per kilogram of latasinumab 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 latasinumab. Previously, we gained alignment from the FDA and EMA to conduct the primary analysis on symptomatic participants in INFRONT3.

Speaker 3

We intend to include the at risk participants in sensitivity analyses. In February 2024, FDA granted latuzinumab breakthrough therapy designation for FTD granulan based on our INFRONT2 Phase two clinical trial data. With this designation, last year we held a Type B interaction with FDA on the potential future biologics license application for latasinumab. The FDA indicated that it would consider the effects of latizinumab on plasma and CSF pro granuline levels as confirmatory evidence, supplementing the potential clinical effects of latizinumab 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.

Speaker 3

Based on the FDA feedback and 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 for latisenumab. In September of twenty twenty four, we presented the patient baseline characteristics for INFRONT3 at the fourteenth International Conference on Frontotemporal Dementias or ISF TD twenty twenty four. The baseline characteristics of symptomatic participants, including age, CDR, plus NACFTLD suboxis scores and NFL levels were representative of the broader FTD granulan registry population based on available registry data. INFRONT3 is designed to provide approximately 90% power to detect a 40% slowing of disease progression. If our trial design assumptions hold, a 25% slowing of disease progression is expected to be statistically significant.

Speaker 3

I'd like to now turn to AL101, our second product candidate in our pro granulant portfolio that we are developing in partnership with GSK. Liklanizinumab, AL101 is a monoclonal antibody designed to block and down regulate the sertilin 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 for use in the treatment of larger indications such as Alzheimer's disease. Our Phase one study in healthy volunteers demonstrated that AL101 was well tolerated and increased progranin levels in plasma and CSF in a dose dependent manner. The ongoing PROGRESS AD Phase II trial AVAIL-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.

Speaker 3

The first participant was dosed just one year ago in February 2024. PROGRESS AD is a seventy six week randomized double blind placebo controlled clinical trial of AL101 designed to assess the safety and efficacy of two doses of AL101 compared to placebo. The primary endpoint of the study is disease progression as measured by the clinical dementia rating Somovoxis. The trial also employs other clinical and functional outcome assessments and biomarkers. We look forward to sharing additional information on PROGRESS AD as the trial advances.

Speaker 3

Finally, on April 5, we plan to present the results from the INVOOC2 Phase two clinical trial, which evaluated the safety and efficacy of AL-two, a TREM2 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. Sarah?

Speaker 4

Thank you, Gary. We are making swift and steady progress in advancing our electobrain 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 cell function. To pursue this aim, we are advancing a portfolio of programs that address both novel and established targets. 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.

Speaker 4

At Elektor, we've worked hard over several years to realize the potential of our proprietary Elektor 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 ABC technology to multiple therapeutic cargos. 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 parenchyma.

Speaker 4

Our ABC technology is used in several of our preclinical programs, including our candidate that replaces GK and our candidates that target amyloid beta and tau pathology. ADP037ABC is our proprietary anti amyloid beta antibody paired with ADC for the treatment of Alzheimer's disease. By leveraging ABC technology, ADP037ABC aims to clear amyloid beta efficiently, thereby reducing plaque accumulation and slowing disease progression, while minimizing the risk of ARIA. It targets a validated epitope specific to brain amyloid beta plaques combined with an optimized antibody constant region to enhance fibocytosis of amyloid beta plaques. In Parkinson's disease, we are advancing ADP050ABC, a GK replacement therapy for GBA gene mutation carriers with Parkinson's disease.

Speaker 4

In these patients, GBA mutations lead to deficient GKs activity. ADP050ABC uses an electro engineered GKs, which is proprietary and has been designed to be more stable and active. ADP050ABC aims to prevent the accumulation of toxic brain sphingolipids 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 GK programs and we are on track to advance them towards IND enabling studies this year.

Speaker 4

We are also developing two tau 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, we 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, Elektra was awarded a $1,700,000 grant from the Michael J. Fox Foundation for Parkinson's Research.

Speaker 4

This funding will support our research on gPNMV, 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 data 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. Mark?

Speaker 5

Thank you, Sarah. As summarized in our fourth quarter and full year twenty twenty four 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.

Speaker 5

Collaboration revenue for the year was $100,600,000 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.

Speaker 5

For 2025, we estimate our collaboration revenue to be between $5,000,000 and $15,000,000 Our anticipated total research and development expenses are estimated to be between $175,000,000 and $185,000,000 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 ElectroBrain carrier 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.

Operator

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

Speaker 6

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 neurodegenerative disease should result in greater clinical benefit and you see a larger separation between active arm and placebo. With that in mind, for the baseline characteristics of INFRONT, I believe twenty two percent of the patients have a CDR FTLD global score of 0.5, 40 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 lotezinumab and placebo? And was there a cap for any of these patient populations?

Speaker 3

Yes. Hi, Tate. This is Gary. Thanks for the question. Good question.

Speaker 3

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 population of FTD granulan. And so as you say, it is always a bit of a balance between trying to treat earlier where we think what we can imagine that there might be more room for greater efficacy, but also including patients that are a little bit further along and may be progressing somewhat faster. So this is what we set out to do and we're very happy that we're able to bring in that very population. We did cap the CDR2s and we reached that cap at stopped enrollment earlier in about two thirds or so through the trial.

Speaker 3

And that was intentional because we didn't want to have too many patients or participants that were had more had been more further progressed and therefore 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 are participants that were have I'm sorry, right, mutation carriers and but had a certain met a certain threshold of NFL, neurofilament 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 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 in 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.

Speaker 3

Why wait if it works in symptomatic subjects, why should patients wait until they're impaired to start treatment?

Speaker 6

So a follow-up on that? Thanks, question B. Yes, actually yes. So when you do look at the NFL levels of those 16 patients that you enrolled that are presymptomatic And then you look at the Gen five data, are they is there an expectation that there's actually going to be progression within those ninety six weeks?

Speaker 3

Yes, good question again. So at the time that the study started, 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 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 Genp and ALLTD group has been published, it now looks like the threshold we used might have would be more along somewhere between two and four years to progress to symptomatic. So that was one of the reasons that we opted to focus our primary analysis on symptomatic subjects. But it's still we still expect some of these patients to have progressed during the study.

Speaker 3

Don't forget, our study is two years long and even some of these subjects have been in for as many as four years now given the long time it took to enroll.

Speaker 2

Okay. All right.

Speaker 6

Thank you very much for taking our questions. Thanks, Pete.

Operator

And the next question will come from Alex Granahan with Bank of America. Your line is open.

Speaker 7

Hey guys, thanks for taking our questions. Just two from us. First on AL101, do you think given the shared pro granuline targeting, there's anything to read through from in the 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.

Speaker 7

Thank you.

Speaker 3

Yes. So maybe this is Gary. I'll start with answer your first question about L101 and hand it off to Sarah. I don't we don't think that there's a read through from the TREN2 trial to this trial just because the mechanisms are so very different. And in this case, we're elevating pibranulin, which we believe is going to have effects probably on lysosomes, and whereas the TRM2 was really a very specific approach to stimulate TRM2 signaling that would increase microglial functions in a different way.

Speaker 3

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 biomarkers that we used and the clinical outcome measures that we used in the TRYM2 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 the biomarkers will serve us very well again in this study in addition to the clinical outcomes and 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 output of 101.

Speaker 3

Did I miss that? Sorry. Yes. Am I correct in that, Alec? Alex?

Speaker 7

Yes. But that I mean both is helpful.

Speaker 3

My mistake. Yes. I thought I heard 2.2. Okay. I'm sorry.

Speaker 3

Yes. I mean, I think we are looking at those I mean, look, I think again, they're different in the mechanism. One is in the case of the onethree study, that's the Phase three study in FTD granulan. These are patients that have a lifelong deficiency or haploinsufficiency of progranulan. And our hypothesis is that by normalizing that in an early stage of the disease, we can slow or stop the disease progression.

Speaker 3

In Alzheimer's disease, it's different. These are more what the genetics 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 progranula levels can be protective against Alzheimer's pathophysiology. So there are a little bit more links certainly than the TRN2, but in the sense that it's all about for granulant.

Speaker 3

But we could imagine scenarios where one might be positive and the other if one were negative, the other could still be positive.

Speaker 4

Okay. I think your question was around our 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 ADP037 ABC, which is our anti amyloid beta antibody, the ABC program.

Speaker 4

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 get to an IND submission and to be in the clinic in 2026. Besides that, we are also applying our ABC technology to target tau and we're taking two different approaches there. One is an antibody approach. The other is with a tau siRNA.

Speaker 4

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 function. Synoptic functions in Alzheimer's disease. And certainly, at this moment, I mean, if you have any other questions around this, I'm happy to answer.

Speaker 7

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

Operator

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

Speaker 8

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 like selecting those as your first two targets? Thank you.

Speaker 4

Yes. I can take that, Mindy. Arnon, you can add. So I think firstly, to get to your question about our Elektor ABC technology, I think it stands out in several ways. I would firstly say that our toolbox approach is versatile and tunable.

Speaker 4

And as you know with ABCs, you're trying to maximize efficacy while minimizing the potential of safety, of tolerability. And I think our technology provides, because provides for that very well because of that sort of versatility. It's not as rigid. We can fine tune both in terms of the affinities, but also in terms of being able to match the right type of fragment 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.

Speaker 4

Now coming to our two different programs, ADP 037ABC, which is RAB amyloid beta technology. We believe that firstly, it targets a validated epitope, which is the pyroglu3 A beta epitope, which is with our brain penetrant ABC. 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 ADP 037ABC to have the potential to be a best in class molecule in the future.

Speaker 4

Now ADP050ABC, which is our GK ABC program in targeting Parkinson's disease. Again, we are developing that. This is our natural GKs is a very unstable and short lived molecule. We've engineered a much more stable and active GK enzyme through mutagenesis, which also has a minimal potential to be immunogenic. And ADP050, again, paired with our ABC technology, really could enable brain penetration and the potential for treatment of Parkinson's disease.

Speaker 4

Great. Thank you all so much.

Operator

The next question will come from Tom Schroeder with BTIG. Your line is open.

Speaker 3

Good afternoon. Thanks for taking the questions. 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.

Speaker 3

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?

Speaker 2

It seems that if the field is moving to SARNA from ASO, it seems that if SARNA have more a better on target activity, sort of fewer side effects, better stability. But yes, we are testing it now and yes, we know 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 SO versus siRNA for example against tau means that there are indications that siRNA is more potent in sort of blocking the target. So it seems that if there are some efficacy advantage as well as safety advantages. So but you're right, this is just an evolving field and we see which of the two nucleic acid technologies is better.

Speaker 2

A

Speaker 3

quick follow-up. 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? Is that something we should be looking for as you out licensing some piece of your technology for some non dilutive funding?

Speaker 2

I mean, the sort of blood and bear chatter is still a technology that multiple companies are seeking means that there are actually sort of few companies with mature blood and barrier technologies and most of the companies with good technologies are sort of 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 inbound interest and there is a lot of interest in our technology. And again, because sort of the convenience of delivery from intravenous sort of the convenience of delivery from intravenous to subcutaneous in the case of Alzheimer's disease, it can sort of reduce or possibly even eliminate ARIA like adverse effects. So I think there is a lot of interest in the technology and I think that even though 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.

Speaker 2

So there is still I think a lot of demand for the technology.

Speaker 3

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

Operator

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

Speaker 7

Great. Thanks for taking my question. I had a question maybe on INFRONT3 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 you're going to continue to follow-up at that point onwards?

Speaker 7

Thank

Speaker 3

you. Yes. Thanks, Ron. Good questions. So the study is powered for approximately ninety percent we have about approximately 90% power to detect a forty percent slowing of disease progression.

Speaker 3

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 I hope that answers your question about the power. The second part of your question was whether it's going to be all the data together.

Speaker 7

Yes, I'm

Speaker 9

sorry, right.

Speaker 3

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 of data on all participants plus data from a long term extension that we'll also also be looking at, which as 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, I'll remind you that we had a meeting with FDA middle of last year under our breakthrough designation status, where we discussed a number of biomarkers.

Speaker 3

And it was very encouraging. They agreed that we came to agreements that we could use in addition to the clinical endpoints, we can also lean into the changes or treatment related changes in progranin levels both in CSF and plasma, which will be considered as confirmatory evidence. And we also discussed a number of fluid and imaging biomarkers that we felt we 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 feeling optimistic that FDA is going to look at the totality of the data and both clinical outcomes and biomarkers.

Speaker 3

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 of the CDR. But if for some reason the unexpectedly the primary endpoint disappoints, I think we're going to have a lot of other potentially supported data that could be give us a backup plan. Thanks, Gerald.

Operator

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

Speaker 10

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 pyroglutamate 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 tretinoinib, which does also use a brain cell technology and kind of how those different epitopes might lead to differentiation? And could you also just remind us if that if thirty seven uses a TFR or a CD98 mediated brain shuttle system? Thanks.

Speaker 4

Yes. So firstly, I mean, if we just go to the trontinumab molecule targets the N terminal region of amyloid beta versus our program ADP0307 targets the pyroglu3A beta epitope, which actually is similar to the epitope in donanumab and remternetect. And I think the second part of your question could you repeat the second part of your question, sorry, Sarah?

Speaker 10

Yes, sure. So like how might the different epitope lead to differentiation in terms of targeting potentially different plaque species?

Speaker 4

Yes. I mean, I think the way we see it is that the because we're targeting the pyroglu3 A beta epitome, which is a validated epitome, certainly that has been demonstrated as a naked antibody to be effective. And so that's wonderful. As you know, the trontinumab molecule is based is a shuttle enabled molecule. The naked molecule, gatinirimab was not effective in the clinic.

Speaker 4

And so I think that bodes really well to using a pyroglut3 A beta epitope in our ABC construct. And then in addition, as I said, we have a fully active Fc and more importantly, we fine tuned our affinity for TFR. I think one of your questions was, are we using TFR and VR for this molecule? We have configured the affinity to TFR to optimize it to have sort of minimal safety RBC reduction and optimal half life and blade penetration.

Speaker 10

Got it. Very helpful. Thank you.

Speaker 3

Thanks,

Operator

Sarah. And the next question comes from Sam Lee with Mizuho. Your line is now open.

Speaker 9

Hi, this is Sam. This is for Gregg Sivanovich. Thanks for taking our questions. A couple on our end. For INFRONT3, can you please remind us how you've enriched for patients to more generally optimize the trial design in order to give yourself the best chance of success for efficacy?

Speaker 9

And also in FTD knowing that there's several programs in clinical development, can you compare and contrast your approach versus the competitive programs? And why you think olatlizumab may offer an optimal therapeutic option when compared to the other programs? Thank you so much.

Speaker 3

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

Speaker 9

Sure. Just repeating the for the first question for INFRONT3, 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 in clinical development, can you just remind us of like the differentiating factors of latuzumab compare, contrast the approach and why perhaps it might offer optimal therapeutic option?

Speaker 3

Yes, thanks. So Luis, thank you for that. So this was a these FTD granular 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 that are difficult to find. I mean, in terms of enriching, we just we really just looked at where the patients were. There were there are pockets of patients in different countries in Italy and Portugal etcetera and other where there are founder effects.

Speaker 3

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. When this trial started, the plan was somewhat optimistically to analyze both the symptomatic and the presymptomatic at the same time. We found that, as I mentioned earlier, that with more data being collected in the observational studies Genphi and ALLFTD, we learned a few things over the time that we were enrolling the study. One is that there was a greater variability of progression in the pre symptomatic because they really don't progress very quickly.

Speaker 3

And for that reason, one reason 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 actually both very pleased that we were doing that. And as I mentioned earlier, we'll also still look at those as pre symptomatic in a sensitivity analysis. In terms of how does our approach differentiate from others, what we do is bring for our mechanism by blocking sertilin 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 inflammatory biomarkers, biomarkers of lysosomal function.

Speaker 3

We saw a normalization of PFAP. We saw a slowing of NFL accumulation. And we also saw changes on imaging on biometric MRI. So and beyond that, we did a density matched comparison of the subjects in our Phase one study to baseline density matched patients from the Genphi study and that showed a slowing of disease progression by up to forty eight percent. So we think we for all those reasons, we believe that this is having an effect on the pathophysiology.

Speaker 3

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 progranulin is a very ubiquitous protein with many functions and we get a little nervous when we think about increasing progranulin levels well above normal, but that our 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 effective, but they're pretty far behind. I mean, we are like I said, we're months away from a readout on our Phase three study and we're quite optimistic.

Operator

I show no further questions at this time. I would now like to turn the call back over to Mark for closing remarks.

Speaker 3

Thank you, operator. Before we end the conference call, I'd just 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 on March 4 in Boston will be there. Lyrics twenty twenty five Global Biopharma Conference the following week will be there March 11 in Miami. And we're also looking forward to SPEAPL's twenty twenty five virtual CNS forum on March 18. Thank you again for your time and attention.

Speaker 3

And we will now conclude today's call.

Operator

Thank you. This does conclude today's conference call. Thank you for participating. You may now disconnect.

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Earnings Conference Call
Alector Q4 2024
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