Good afternoon, ladies and gentlemen, and welcome to the Elector Second Quarter and Mid-Year 2025 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 the session, you will need to press star 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. As a reminder, this conference call is being recorded. I would now like to turn the call over to Katie Hogan, Senior Director of Corporate Communications and Investor Relations. Please go ahead.

Thank you, Operator, and hello, everyone. Earlier this afternoon, we released our financial results for the second quarter, 2025. The press release is available on our website at www.elector.com, and our 10-Q was filed with the Securities and Exchange Commission this afternoon. Joining me on the call today are Dr. Arnon Rosenthal, co-founder and CEO, Dr. Sarah Kankari-Mitra, President and Head of Research and Development, Dr. Giacomo Salvadori, Chief Medical Officer, Neil Berkley, Chief Business Officer and Interim Chief Financial Officer, and guest speaker, Dr. Ryan Darby, Associate Professor of Neurology and Director of the Frontal Temporal Dementia Clinic at Vanderbilt University Medical Center. as well as a paid consultant to Elector, who will provide clinical context on frontal temporal dementia. After our formal remarks, we'll open the call for Q&A. I'd like to note that during this call, we'll be making a number of forward-looking statements. Please take a moment to review our slide on the webcast, which contains our forward-looking statement disclosure, and 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?

Thank you, Katie, and good afternoon, everyone. As we enter the second half of 2025, Electo is approaching an important inflection point. By mid-first quarter, we expect top-line data from our pivotal phase three in front three trial of platosinamab, our most advanced clinical program. This trial represents the first rigorous test of progranuling-elevating approach to treating frontotemporal dementia due to the GRN gene mutation, a fatal and rare form of dementia that strikes people decades earlier than Alzheimer's disease and currently has no approved therapy. We designed latozinamab based on clear biological and human genetic rationale to elevate progranuling levels by blocking its and degradation by sotilin receptor. FTD-GRN is directly caused by progranuline deficiency, and restoring it has the potential to alter the cause of the disease. Our earliest studies in participants with FTD-GRN provided encouraging signals, both in biomarkers and in clinical progression. In front three will allow us to determine whether those findings hold up in a larger placebo-controlled double-blinded trial. Together with our partner GSK, we are advancing lunch readiness activities to help ensure we are well-positioned to support the potential commercializations of lactosinamac. Additionally, we are also excited about our late-stage clinical program in early Alzheimer's disease, where we are advancing AL-101, our second progranuling-elevating antibody, which is currently in phase two trials. There is a strong genetic and biological rationale for the role of progranuling in Alzheimer's Loss of function mutations in progranuling have been shown to increase the risk of Alzheimer's disease in humans while overexpression of progaloling has been shown to be protective in animal models of Alzheimer's disease. Enrollment of this phase two trial was completed in April and trial completion is expected in 2026. AL101 shares a similar mechanism with Latozinamab but its pharmacological properties makes it suitable for more prevalent no degenerative diseases. In parallel, we are investing in a research and preclinical pipeline designed to fuel our future. These programs include our proprietary anti-amyloid beta antibody for Alzheimer's disease, an engineered GKs enzyme replacement therapy for Parkinson's disease, and an anti-tau siRNA for Alzheimer's disease, all enabled by electric brain carrier. Our proprietary technology platform that enables us to deliver antibodies, proteins, enzymes, and SIRNA across the blood band barrier. This opens the door to more effective brain-directed therapies across multiple modalities. Our late-stage clinical program combined with our early-stage pipeline enabled by our proprietary bloodline biotechnology gives us the opportunity to deliver both near-term catalysts and sustained pipeline momentum. Our goal is to deliver therapies that eradicate neurodegeneration and improve patients' outcomes And in doing so, build a durable, high-impact biotechnology company. Our commitment to tackling neurodegeneration drives us to engage experts who understand these diseases firsthand. It is my pleasure to introduce Dr. Ryan Darby, Associate Professor of Neurology and Director of the Frontotemporal Dementia Clinic at Vanderbilt University Medical Center. Dr. Darby brings deep clinical expertise in frontotabral dementia, and will speak to the urgent and met need in this disease. Dr. Darby received his undergraduate degree from Princeton University in psychology and neuroscience, and his medical degree from Vanderbilt University. He trained in neurology at MGH and Brigham and Women Hospital as part of the Partners of Neurology Harvard Medical School program. Dr. Darby's research focuses on neurodegeneration's impact on brain networks related to behavior and decision-making. His contributions to the field have been recognized with awards such as the Norman Gershwin Prize in behavioral neurology. Dr. Darby, thank you for joining us today. I will now turn the call over to you.

Thank you so much for the kind introduction. Today I'll be providing an overview of frontotemporal dementia, or FTD, which is a complex and devastating group of neurodegenerative conditions that impact thousands of individuals and their families worldwide. We'll touch on its subtypes, the clinical progression, the genetic drivers like FTD, GRN, and the current and future landscape of treatment and diagnosis. FTD is not a single disease, but instead a group of disorders caused by progressive neuronal cell loss in the brain's frontal and temporal lobes. This neurodegeneration leads to a broad range of symptoms, and we categorize FTD into different clinical subtypes based on those symptoms and the areas of the brain that are affected first. First, we have the behavioral variance FTD, or BVFTD, which is the most common form. It's characterized by striking changes in personality and behavior, such as apathy, impulsivity, and socially inappropriate behaviors. Next, there's primary progressive aphasia, or PPA, which primarily impacts language. In FTD, this is further subdivided into two main subtypes, the semantic variants, where individuals lose their understanding of word meaning, and the non-fluent variant, where speech becomes halting and effortful. Finally, we have FTD that presents with motor or movement-related symptoms, and this can present with overlapping conditions such as progressive supranuclear palsy, or PSP, corticobasal syndrome, or CVS, and ALS-FTD, which combines features of motor neuron disease with FTD. These clinical presentations fall under the broad umbrella term frontotemporal lobar degeneration, or FTLD, which is the pathological term reflecting that underlying biology. FTD is most commonly associated with the buildup of two key proteins, TDP43 and tau. However, determining which protein is involved in a living patient is extremely difficult unless there's a known genetic mutation or after death at a postmortem examination. FTD itself is more rare than Alzheimer's, but is still the most common cause of dementia in individuals under the age of 60. In the U.S., the incidence is estimated to be 15 to 22 cases per 100,000 person years, which results in a prevalence of about 50 to 60,000 concurrent cases in the U.S. In Europe, the number is closer to 110,000. The toll on individuals and their families in FTD is profound. FTD compared to other dementias often leads to greater functional impairments in the activities of daily living, earlier onset, frequently disrupting careers, relationships, and independence. Caregivers in FTD often report a higher burden and more painful loss of sense of personal identity and personhood compared to Alzheimer's disease, in part because these patients are presenting with emotionally disengaged symptoms and inappropriate behaviors. Approximately 30% of FTD cases have a strong family history. We now recommend that there are three main autosomal dominant genetic mutations in FTD. The C9ORF72 mutation, the MAPT mutation, and the GRN mutation. There's at least 20 other rare mutations that are also known to be associated with FTD. Today we're focusing on FTD-GRN, which represents about 5 to 10 percent of FTD cases. This is a form that results from mutations in the GRN gene, leading to reduced levels of progranulin, a critical protein for neuronal survival and function. Progranulin deficiency contributes to neurodegeneration through multiple potential mechanisms, including lysosomal dysfunction and inflammation. Emerging biomarkers, such as neurofilament light chain, or NFL, and changes in structural brain MRIs are helping us to track disease progression and onset of neuronal loss more objectively. Unfortunately, there are no FDA-approved disease-modifying treatments for FDV. Management currently is largely symptomatic and supportive, often involving behavioral strategies, speech therapy, and medication targeting mood or agitation. However, there is hope on the horizon. With ongoing clinical trials now targeting genetic forms of FTD, including GRN mutations, this offers an exciting opportunity to address the disease at the molecular level and develop new therapies. However, we face several key challenges. First is the diagnostic complexity. FDD is frequently misdiagnosed or diagnosed late in the disease course. Genetic testing is not routinely performed, and even in younger patients, we often lack information about the underlying protein pathology, making it difficult to tailor interventions or enroll appropriate patients in clinical trials. Trial design is another challenge. Symptoms vary widely, not just from patient to patient, but even in the same person over time. And that can include the full range of behavioral, psychiatric, language, and motor features. We need better tools to identify patients earlier in that disease course and better ways of tracking that disease over time. Finally, there is an urgent need for disease-modifying therapies, especially in the genetic subtypes where the biology is known. Advances in biomarkers are helping move the field forward by enabling early diagnosis, better stratification, and more sensitive tracking of disease progression. So, in closing, FTD is a complex and deeply impactful disease, both biologically and also personally for the patients and families. With increased understanding of the genetic underpinnings like GRN mutation and the development of robust biomarkers, we're now in the position to truly develop transformative therapies. So with that, I'll turn the call over to Giacomo Salvador, Elector's Chief Medical Officer.

Thank you, Dr. Darby, for that insightful overview of the clinical realities in urgent and unmet need in front of temporal dementia. Your perspective helps frame the importance of our work as we approach the in-front free data readout by Meet Q4. As Dr. Darby noted, FTD-GRN accounts for approximately 5% to 10% of all FTD cases. This represents about 8,000 to 17,000 cases in the U.S. and E.U. alone. It is striking how many people living with FTD still have no approved treatment options today, underscoring the need for continued innovation and urgency in this field. With this context in mind, I want to provide a deeper overview of the science behind our approach, the data we have generated to date, and how our pivotal phase 3 in FRON3 trial is structured. Latozinemab is a novel investigational human monoclonal antibody developed in collaboration with GSK, and we believe it is the most advanced therapeutic candidate in development for FDD-GRN. We have evaluated latozinemab in both Phase I and Phase II clinical studies. In Phase I, the treatment was well-tolerated in healthy volunteers, and those dependent increases in plasma progranulin were observed. Our open-label Phase II INFRON2 study enrolled 12 participants with symptomatic FTD-GRM. Treatment with latozinimab, normalized plasma, and CSF programming levels, resulting in a two- to three-fold increase that was rapid and sustained over the course of treatment. We also assessed a panel of disease-relevant biomarkers, including neurofilament light chain, NFL, glial fibrillary apidic protein, GFAP, and markers of litosomal function and neuroinflammation. These biomarkers moved in the direction consistent with slowing disease progression. On the clinical side, we used the CDR-PLUS-NAC FTLD-SB, a validated scale for FTD that captures cognitive, functional, behavioral, and language changes. In a blinded propensity match comparison to participants from the GenPhi2 Natural History study, treatment with latosinimab was associated with a 48% slowing of disease progression over 12 months. These are the same clinical measures and core biomarkers being carried forward into INFRON3, our ongoing pivotal phase 3 trial. INFRON3 is a 96-week randomized double-blind placebo-controlled global trial, evaluating latosinimab being 103 symptomatic, and 16 at-risk individuals with confirmed GRN mutations. Participants received 60 mg per kg of latosinamab, or placebo, via intravenous infusion every 4 weeks. The primary analysis will be conducted in symptomatic participants, and we plan to include at-risk participants in a sensitivity analysis. The clinical primary endpoint is the CDR plus NAC FTLD sum of boxes. Following engagement with the FDA and in line with the agency's recommendation, we and GSK had made the decision to amend a statistical analysis plan for Infrontree to include plasma progranulin as the co-primary endpoint along with the CDR plus NAC FTLD SB. Keep in mind that an approximate 50% reduction in progranulin is a causal factor for STD-GRN. Additionally, we are collecting fluid and imaging biomarkers, including plasma NFL, GFAP, and volumetric MRI. We believe this positions are to deliver a clear and well-aligned data package later this year. INFORM3 is approximately 90% powered to detect a 40% slowing of disease progression. If our key design assumptions hold, a 25% slowing is expected to be statistically significant, and we believe that will represent a meaningful clinical benefit in a disease with no approved treatment. Latosinemab has been generally well tolerated across our clinical trials, with no major safety signal observed to date in either healthy volunteers or patients with STD-GRM. As a reminder, latosinemab has received breakthrough therapy and fast-track designations from the FDA and orphan drug designation from both the FDA and the EMA. Following the receipt of the breakthrough therapy designation, which was granted based on our phase 2 data, we had a type b interaction with the fda to address key elements of a potential future biologic license application the agency indicated that the totality of the evidence including clinical outcomes and disease relevant biomarker could support a submission for full approval pending bla review additionally we aligned on a set of fluid and imaging biomarkers that may serve as supportive efficacy data. We and GSK are preparing for potential BLA and MAA submissions in 2026, seeking full approval based on the strength of our trial design. Latosinamab represents a biomarker-driven, mechanistically targeted approach to treating genetically defined FTD-GRN, a severe neurodegenerative disease with no approved therapies. We believe the strength of our clinical data, the alignment with regulators, and the breadth of our clinical and biomarker package position us well as we prepare for the Infront 3 readout by meet Q4. Let me also briefly comment on AL-101, our second progranulin-elevating monoclonal antibody. DL101 is a distinct molecule that targets a different epithoponsorilin and has a different pharmacokinetic and pharmacodynamic profile, making it suitable for more prevalent neurodegenerative diseases. Importantly, as Arnon mentioned, our rationale for evaluating a progranulin-elevating approach in Alzheimer's disease is grounded in human genetics. Reduced GRN expression has been implicated in Alzheimer's pathophysiology, supporting the potential of programming modulation in that setting. AL101 is currently being evaluated in early Alzheimer's disease, with enrollment in the Global Phase II Progress AD study completed in April and trial completion expected in 2026. With that, I'll now turn the call over to Sarah to share an update on our preclinical and research pipeline.

Thank you, Giacomo. As you've heard today, we are advancing our late-stage clinical programs, which have a strong scientific rationale, robust trial designs, and meaningful regulatory engagement. In parallel, we are advancing a research and preclinical pipeline that reflects electors' long-term vision. These programs are grounded in the same principles that define our clinical portfolio, a strong genetic and biological rationale, and high translational potential, and a focus on serious neurodegenerative diseases with first- and Western-class therapeutic approaches. A key enabler of our preclinical and research programs is our proprietary electrobrain carrier. Delivery of sufficient drug to the brain remains a challenge for targeting neurodegenerative diseases. Our ABC platform is a versatile blood-brain barrier transport technology that allows us to efficiently deliver a broad range of therapeutic modalities into the brain. These include antibodies, proteins, enzymes, and siRNA. By selectively applying the ABC platform to drug cargos, where enhanced brain delivery can address known limitations of efficacy or safety, we believe we can expand what is possible in the treatment of neurodegenerative diseases. Our preclinical programs include a brain-penetrant anti-amyloid beta antibody for Alzheimer's disease, where a significant unmet need remains despite the approval of anti-amyloid beta antibodies. These approved antibodies have delivered plaque clearance, but only modest clinical benefits, and they are associated with side effects, such as amyloid-related imaging abnormalities or ARIA, which limit their use. As a result, the field is increasingly focused on brain-penetrant anti-A-beta antibodies that aim to increase efficacy, reduce the incidence of ARIA, enable subcutaneous delivery, and the possibility of prevention therapy. Our anti-amyloid beta antibody, ADP037ABC, is designed to deliver on these goals. It combines a validated anti-A-beta epitope, a tailored FC region, supporting robust plaque clearance, and our proprietary brain delivery ABC platform. While an emerging brain-penetrant anti-amyloid beta antibody has shown improved brain exposure and reduced incidence of aria in the clinic, it has introduced anemia related to transferrin receptor engagement on erythroid precursor cells as a safety concern. ADP037ABC also uses the transferrin receptor for transport, but it is specifically engineered to minimize anemia risk while enhancing amyloid beta clearance. With these features, we believe that ADP037ABC has the potential to be a best-in-class anti-amyloid candidate. Another program I'd like to highlight is ADP050ABC, our engineered GKs replacement therapy. Mutations in the GBA1 gene lead to reduced activity of the lysosomal enzyme glucocerebrosidase, or GKs, and are associated with Gaucher disease, Parkinson's disease, and Lewy body dementia. While enzyme replacement therapies are approved for the peripheral manifestations of Gaucher disease, these therapies do not cross the blood-brain barrier and therefore have limited impact on neurological symptoms. With ADP050ABC, we aim to deliver an engineered, more stable, active form of GKs to the brain, potentially restoring lysosomal function in nerve cells and ultimately countering the brain pathologies associated with Gaucher disease, Parkinson's disease, and Lewy body dementia. Beyond these two programs, we continue to develop a focused set of research stage candidates addressing neurodegeneration through the removal of toxic proteins, replacement of deficient proteins, and restoration of immune and synaptic function. These include a brain-penetrant tau-targeting antibody, a brain-penetrant anti-tao siRNA, and a aurelian modulator. With that, I'll turn the call over to Neil to provide an update on our financials.

Thank you, Sarah. As summarized in our second quarter 2025 financial results, which we made available after the market closed today, we are in a strong position to deliver against our strategic objectives. groups. We close the quarter with $307.3 million in cash, which we continue to expect will provide runway into the second half of 2027. We have updated our 2025 financial guidance. We anticipate collaboration revenue to be between $13 million and $18 million, our total research and development guidance to be between $130 million and $140 million, and our total general and administrative guidance to be between $55 million and $65 million. Our financial position enables us to stay focused on execution across our late-stage clinical, preclinical, and research pipeline. 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. at this time we will conduct the question and answer session as a reminder to ask a question you'll need to press star one one on your telephone and wait for your name to be announced to withdraw your question please press star one one again please stand by while we compile the Q&A roster our first question comes from the line of Tom Schrader of BTIG your line is now open good afternoon thanks for taking the questions uh i just wanted to clarify in the statistical analysis plan is the only change that you've added progranulin or is there something else there

and just give us a sense of why you added that the progranulin i mean on average it it uh normalized but did it normal does it normalize in every patient in your prior trials i'm just trying to understand why you're doing this. And then on the ABC portfolio, is it mostly transferring receptor-based or are you using other receptors?

Thank you.

Thanks for your question. This is Giacomo Salvatore, the chief medical officer. The change in our statistical analysis plan to include progranuline as a co-primary endpoint was reactive to a specific request by the FDA, by a statistical reviewer by the FDA, who asked us to make this change to the statistical analysis plan and recognizing the important mechanistic role of progranuline. This is the only change made following a specific comment by a statistical FDA reviewer. Regarding your question about the effect on progranuline in the population of patients with FDD-GRN, we have analyzed plasma progranuline in the phase 2 study and we showed a 2 to 3-fold increase in progranuline after treatment with latozinamab. Overall, we believe based on our phase two data, as well as the longitudinal data from observational studies, we feel we believe that we have more than 99 percent power to show statistically significant effect on programming.

Maybe I'll take the question on the ABC platform, Tom. So, yes, while we are exploring other transporter-related, you know, transport vehicles, our lead programs that we are talking about do depend on the transfer and mediated process.

Okay, great.

Just to add to you, Giacomo, we are not aware of any case where we treated paid in sea elevation. So for galoling, it's consistently being elevated in STD mutations.

Right. Thank you.

Our next question comes from the line of Myles Minter of William Blair. Your line is now open.

Yeah. Following on from Thomas' first question, why did that reviewer request plasma progranulin? Like, this is an antibody, I assume it's largely peripherally restricted with some minimal getting into the brain. I know tapping these patients in terms of CSF and measuring progranulin is probably problematic at this stage. But is that reviewer, like, are they basically agreeing that plasma for granuline with a largely peripherally restricted antibody driving that upregulation is predictive of functional benefit in a CNS disorder like frontotemporal dementia? That's the first one. And then if Dr. Dove is still on the line, I think in front three at its bare minimal was powered to show a 25% improvement in the slowing of cognitive decline in this trial. Just on the background of what we've seen with the uptake of anti-amyloid therapies in Alzheimer's disease showing a 27% slowing of decline, I know there's some safety concerns with that. But if it was 25%, is that still an attractive product to prescribe to this patient population? Thank you very much.

Thank you very much for your question. So the FDA didn't provide detailed rationale for their input on the analysis plan and rationale behind their suggested change and elevating programming at co-primary endpoints. We believe that the FDA input underlines the importance of programming as a biologically meaningful marker. in FDD-GRN. Mutation of in progranulin gene, in granulin gene leads to uproinsufficiency and is a known case of the disease. Another point to underline is the fact that we had prior discussion with the FDA and we disclosed those in previous calls and we had an agreement that elevation of progranulin could subserve as confirmatory evidence in our latozynema program. So this change follows some previous discussion that we have disclosed before. Regarding your second comments on peripheral versus central, In the phase two study, we were able to show robust increases of progranulin, two to threefold, both in the CSF as well as in plasma. Therefore, our previous data indicates a strong effect no matter what the compartment is chosen to study progranulin elevation.

There is a really good between the zero asthma progranuling appear to be a good representation of what actually will also happen.

Hi, this is Ryan Darby.

I can answer the other question if now's the right time. Yes. So in terms of that clinical benefit, you know, I think a 25% reduction would be something that would be meaningful in a disease where we don't have any other therapeutic options. I think in the anti-amyloid infusion comparison, you know, the issues with implementation there I think center around the side effects and that cost-benefit profile that we're discussing with patients where some patients, you know, would opt away from that. I think in FTD with no other viable treatment options, there would be more of an interest in that. It would obviously depend on the other side effect profile and what that looked like.

Beautiful. Thanks for the questions.

All right. Thank you.

Our next question comes from the line of Alex Stratahand of Bank of America. Your line is now open.

Hey, guys. Thanks for taking our questions. One on AL001 from us as well. Curious how changing the SAP at this stage could affect powering on the modified CDR small boxes since plasma with PGRN is now a co-primary. And in your discussions with the FDA and or GSK, I'm curious if expanded enrollment in FRONT 3 was part of your discussions at all. And given the FDA's apparent focus on PGRN levels, have you gotten a sense whether plasma PGRN could make its way onto the label as well for selection?

Thanks. Thanks for your questions. So, to start, regarding how the change in the SAP to include programming as co-primary affects the power or affect the conduct of the study, I can tell you that with adding two co-primary endpoints, one clinical, this is the CDR, FTLD, some of boxes and progranulin, we need to show statistically significance on both co-primary endpoints for the study to be positive. Having said that, these two co-primary endpoints are analyzed independently, meaning that the power regarding the CR sum of boxes remain unchanged. And as I said before, regarding progranulin, based on our phase two data, we have more than 99% and power to show its immediate effects on elevating programming. The other – sorry, can you repeat the other question?

Yeah, just given the focus of the FDA on plasma PGRN, I'm curious if this could be, you know, a potential – Yeah, yeah. – as with the population on the label.

Yeah, we haven't had any discussions about labeling, and we will entertain discussions with regulators after we have the trial readout in mid-Q4 2025, but we didn't have any discussion about programming being part of the label. Understood. Thank you very much.

Thank you. Our next question comes from the line of Yaron Werber of TD Securities. Your line is now open.

Thank you very much for the question. This is Stephen Ionov on for Yaron Werber. Did the FDA mention any particular threshold that they wanted to see for progranulin, or is that just statistical significance? And then to follow up, you mentioned the 90% power to see a 40% lowering. Are you tying that in any way to the progranuline level, or is that just still the sum of boxes on point?

Sure. The FDA didn't specify any particular threshold regarding the elevation of progranuline that they would want to see based on our trial data. They simply provided a comment that they recommended us to include progranulin change as co-primary endpoint. Then the other question was about the powering and the studies power for 40% as I mentioned just now the CDR boxes and programming have analyzed separately so the initial assumption regarding the CDR remain unchanged and we there is no change, you know, know regarding the CDR sum of boxes and programming we are 99% powered based on our phase two data so it doesn't we don't think it's gonna affect the probability of success overall but considering the fact that we in order for the site to be positive we need to show significant on both primary point to add again that even if we see 25% a slowdown in cognitive decline this will be statistically significant clinically meaningful and will most likely be approvable understood thank you very much thank you

our next question comes from the line of Sean Lommen of Morgan Stanley your line is now open.

Hi. Hi, this is Mike Riyad on for Sean. Thank you for taking our questions and congratulations on completing Enrollment for Progress. We have two questions. First one for Dr. Darby. We'd love to hear your thoughts. Assuming success restoring progranuline to normal levels and FTG progranuline, like flowing CDRSB, would that increase your confidence in elevating progranuline above endogenous levels, like being beneficial to patients with Alzheimer's?

Yeah, that's an interesting question. You know, I think that certainly showing that you can modify the level and have a benefit would help support that. I don't know if I would move you all the way to saying that supranormal levels would have increased benefit, if I'm understanding that question. But certainly restoring to normal levels, you know, shows that the intervention can do that. and if it's associated with a clinical benefit, that it can have an impact.

Oh, thanks. That makes sense. And then maybe just, sorry, just a quick follow-up, what would be, like, your view on, like, other FTD subtypes?

Yeah, I mean, I think it would definitely make me curious of seeing what that effect could potentially be so that, you know, if this is protective, would going even above the normal levels be helpful? I think it would open up that possibility possibility, or if there is a subset of patients with relatively lower, you know, even if it's not to the level of progranulin carriers, would that be a good treatment target? And then you'd be able to show that there is something that is potentially able to do that.

Thank you so much. That's really helpful. And then I guess my follow-up question would be for management. In Fund 3, given the potential for interpatient variability on baseline progranulin level, be it by stage of disease or other factors, be it like semantic or motor disruptions, like how are you normalizing for that? Is it like the FDA requesting like a within-subjects comparison from baseline to the study end, or is it more like an aggregate comparison between study arms?

I can take this one. So, we are finalizing the SAP in close discussion with the FDA, and we are going to analyze plasma programming change in the active arm versus placebo. So we didn't have any specific request. I can add the fact that upload insufficiency in the granuline gene is associated with 50% reduction of programming levels. And this is enough to produce a disease phenotype, meaning that 50% decrease in progranuline level are almost invariably associated with frontotemporal dementia and development of the full-blown disease. Our previous data showed two, threefold elevation of plasma progranulin, and also the CSF data are very consistent with that, and we were able to show normalization of those levels in individuals who had baseline deficits. So, Arnon, I don't know if you want to add anything, but we see consistently low levels of progranulin in patients with FTDGR. And this is a functional mutation which is associated with the disease phenotype.

Yes, mechanistically the mutations that cause frontotemporal dementia are full heterozygous loss of function. These are coding mutations that lead to complete ablation of the mutated protein. There's no gradation in the mutated protein. So every individual that has mutations that cause frontotemporal dimensions are conning mutations that lead to haploid insufficiency, like 50% or less of the progranuline. The promoter mutations are actually the three-prime untranslated mutations that you refer to are a different class of mutations. These are mutations that are associated with very modest reduction in progranoling of 10 to 15 percent, and they are associated with other diseases like Parkinson's disease and Alzheimer's disease, but they don't lead to frontotemporal dementia.

Thank you so much. That's been really helpful. I appreciate all the call here.

Thank you.

Our next question comes from the line of Greg Zuvanovic of Mizuho. your line is now open hi there this is Doug McPherson on for Greg thank you very much for having me on and taking my call or question rather so thinking about the relative subjectivity of the endpoints of clinician severity score and the rating scales compared to biomarker data is there anything that can be done or has been undertaken in order to try to minimize perhaps a placebo effect or to optimize for like this spread or separation between active

drug and placebo thanks for the question the powering of the study take into account also the expected placebo change based on the natural history data and the natural course of the disease. Regarding biomarkers, they are unlikely to show any effects, any placebo effect, because those are objective measures uh nfl as well as gfap and volumetric mri there is not you know there is um no no placebo effect as far as we know um regarding um broadly speaking the placebo effects on clinical measures uh what we know from the neurodegenerative diseases is that if platybo effects are present at all. They typically tend to be manifest in the first few weeks of treatment and they tend to dissipate over time. Our trial are, the infantry studies, 96 weeks long and in a disease that show progression over time. So we don't see the platiboid fat as a particular risk for this kind of indication.

Sure. Thank you for that. Appreciate it. And then a quick follow-up. Should we at all be concerned about ARIA for TRAEs? And if so, what would be sort of an acceptable ARIA prevalence or severity in treated patients?

Yeah, you're asking about which program in particular?

Oh, I'm still on the FTD phase 3 study.

So we are monitoring blind safety periodically, and there is an independent monitoring committee which oversees the safety of the drug as well, and we didn't have reports of ARIA in the study in Front 3.

Oh, that's great to hear. Thank you.

So, you know, maybe if I can add one quick thing, you know, typically ARIA is observed in Alzheimer's disease and trials and it's associated with the removal of amyloids from the brain, especially from the vasculature. So in the absence of amyloid or when it's not a prominent feature of the disease, I think the biological rationale for underlying the physiology is not present.

I just wanted to clarify this.

So that's why it's not expected as a feature of this treatment, and we haven't observed it so far.

That's great to hear. Thank you very much. I appreciate you taking the question.

Sure. Thank you. Our next question comes from the line of Paul Mateus of Stiefel. Your line is now open.

Hi, this is Emily on the Paul. We were just wondering if there was a situation where you were able to hit on progranulin, but the clinical data was a bit more equivocal. How would you feel about your chances at approval in that situation? Thanks.

Sure. Thanks for the question. So, So, the study in Front3 is enrolled 103 subjects with symptomatic STDGRN, we collect a number of clinical measures as well as biomarkers and we will be, if the data is supported, we will be pursuing full approval. Based on the data, and given the fact that there are no approved treatments, and there is a disease with a very huge burden, as Dr. Darby reminded us just earlier, we will be open to have a dialogue with the regulatory authorities and the FDA based on the observed findings, which may include changes in progranuline. But again, we are meant to pursue full approval if the data supports it. And what we know from the TNS space, the FDA has recently approved drugs that we have based on biomarker findings if we think about the approval of TOFERS and in SOD1 ALS. So, there are regulatory precedents, especially in CNS diseases, which are rare and with no approved treatment options. But we are pursuing full approval if there is a support.

Thanks. And then just one follow-up. Were you able in that meeting the FDA to confirm your sample size, confirm alignment on the sample size again? Thank you.

Yeah, sure. Thanks for the question. So, we aligned on the sample size with the FDA in a meeting that we had in 2023, where we performed the blinded sample size re-estimation, and we observed the lower viability on the primary outcome measure the cdr sum of boxes at tld as we we we had in mind in our original powering assumptions so uh we agree with the fda the sample size between 90 and 100 subjects would be sufficient to show uh 40 percent uh showing all this progression in the active arm with latus dinamab versus placebo, and we got an agreement with them on the sample size and we enrolled 103 subjects, so over, slightly over the number that we think it's needed to show the clinical extract.

Thanks.

Thank you.

Our next question comes from the line of Pete Stavropoulos of Cantor Fitzgerald. Your line is now open.

Hi, this is Samantha Schaefer on the line for Pete. Thanks so much for taking our question. So a question for the team, Dr. Salvador, Dr. Darby related to Infront 3. We know that 16 asymptomatic patients were enrolled who will not be included in the primary analysis. Based on their baseline NFL levels, though, and what we know about natural history, do Do you expect signs of progression and potential differences between Latozzi and placebo within the 96 weeks? And then I just have a follow-up question.

Sure. Thanks for the question. So, as you correctly said, the primary population is our patients who are symptomatic. So these 103 subjects, as I just mentioned, asymptomatic subjects, 16 of them were enrolled in the trial and will be part of sensitivity analysis the study is ongoing and remain blind so we I cannot comment on what we expect or what we in terms of the ability to see an effect in pre-symptomatic subjects we will definitely look at the data and part of the analysis and possibly entertain in discussions with the regulators based on the results that we observed.

To add to this, the recruitment of the pre-symptomatic patients, as you said, based on genetic mutations of phototemporal dementia and certain threshold level of neurofilament, a sort of published study suggested that such patients could convert to symptomatic within the two-year period. But we will have to see what's the actual data of the clinical trial. But that was the original expectations and the rationale for recruiting this group of pre-symptomatic with high level of neurofibre.

That's very helpful. And just to follow up, we know that there's a part two of the in-front study on an open label extension. Can you give us a sense, maybe quantitatively or qualitatively, how this part of the study is progressing? Is there a high rollover rate into the OLE?

So we haven't disclosed details on how many subjects rolled over into the OLE. As a company, I can say that we are satisfied regarding the number of subjects who are actually opting in to the open level extension, and we think that it will provide meaningful data about the persistence of the benefit in terms of clinical endpoint and biomarkers as well as what happens in subjects who switch from platibo to active treatment, moving to the open level extension. There are some very interesting and meaningful precedents in the TNS space about how this open level extension data can provide more clarity on the meaningfulness of the results from the double-blind portion of the study. So we are, you know, we remain interested in looking at the results. But again, the statistical, I mean, the analysis will be focused on part one, which is the double blind portion of the study, 90 this week. So we will not, you know, we will not focus on the open level extension for now.

Great. Thank you guys so much.

Thank you. I am showing no further questions at this time. I would now like to turn it back to Neal Berkley for closing remarks.

Thank you. Before we end the conference call, I would like to share that Elector will be participating in a number of upcoming conferences, including the 2025 Cantor Global Healthcare Conference on September 4th in New York, the Morgan Stanley 23rd Annual Global Healthcare Conference on September 8th in New York, and the HC Wangwright 27th Annual Global Investment Conference on September 9th in New York. Thank you again for your time and attention. We will now conclude today's call.

Thank you. This does conclude the program. You may now disconnect.