Q2 2025 Alector Inc Earnings Call
Speaker #1: Good afternoon, ladies and gentlemen, and welcome to the Alector Second Quarter and Midyear 2025 Earnings Conference Call. At this time, all participants are in a listen-only mode.
Speaker #1: 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 *11 on your telephone.
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Speaker #1: I now like to turn the call over to Katie Hogan, Senior Director of Corporate Communications and Investor Relations. Please go head.
Speaker #2: Thank you, Operator, and hello, everyone. Earlier this afternoon, we released our financial results for the second quarter of 2025. The press release is available on our website at www.elector.com.
Speaker #2: And our 10-Q was filed with a this afternoon. Joining me on the call today are Dr. Arnon Rosenthal, co-founder and CEO; Dr. Sarah Kenkare, Mitra; President and Head of Research and Development; Dr. Giacomo Salvadore, Chief Medical Officer; Neil Berkeley, Chief Business Officer; and Interim Chief Financial Officer.
Speaker #2: 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.
Speaker #2: After our formal remarks, we'll open the call for Q&A. I'd ike to note that during this call, 'll be making a number of forward-looking statements.
Speaker #2: 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.
Speaker #2: I would now like to turn the call over to Arnon Rosenthal, Chief Executive Officer. Arnon?
Speaker #3: Thank you, Katie, and good afternoon, everyone. As we enter the second half of 2025, Elector is approaching an important inflection point. By mid-first quarter, we expect top-line data from our pivotal Phase III and Front III trial of Latozinumab.
Speaker #3: Our most advanced clinical program. This trial represents the first rigorous test of prevalently elevating approach to treating frontal temporal dementia due to the GRN gene mutation.
Speaker #3: A fatal and rare form of dementia that strikes people decades earlier than Alzheimer's disease, and currently has no approved therapy. We designed Latozinumab based on clear biological and human genetic rationale, to elevate progranulin levels by blocking its internalization and degradation by serotonin receptor.
Speaker #3: FTDGRN is directly caused by progranulin deficiency. And restoring it has the potential to alter the cause the disease. Our earliest studies in participants with FTDGRN provided encouraging signals both in biomarkers and in clinical progression.
Speaker #3: In Front III, we 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 launch readiness activities to help ensure we are well positioned to support the potential commercialization of Latozinumab.
Speaker #3: Additionally, we are also excited about our late-stage clinical program in early Alzheimer's disease, where we are advancing AL101, our second progranulin-elevating antibody, which is currently in Phase II trial.
Speaker #3: There is a strong genetic and biological rationale for the role of progranulin in Alzheimer's disease. Loss of function mutations in progranulin have been shown to increase the risk of Alzheimer's disease in humans while overexpression of progranulin has been shown to be protective in animal models of Alzheimer's disease.
Speaker #3: Enrollment of this Phase II trial was completed in April, and trial completion is expected in 2026. AL101 shows a similar mechanism with Latozinumab, but its pharmacological properties make it suitable for more prevalent neurodegenerative diseases.
Speaker #3: In parallel, we are investing in a research and preclinical pipeline designed to fuel our future. This program includes our proprietary anti-amyloid beta antibody for Alzheimer's disease, and engineered GKS enzyme replacement therapy for Parkinson's disease, and an anti-Tau SIRNA for Alzheimer's disease.
Speaker #3: All enabled by Elector brain carrier. Our proprietary technology platform that enables us to deliver antibodies proteins enzymes and SIRNA across the blood-brain barrier. This opened door to more effective brain-directed therapies across multiple modalities.
Speaker #3: Our late-stage clinical programs combine with our early-stage pipeline, enabled by our proprietary blood-brain barrier technology, gives us the opportunity to deliver both near-term catalysts and sustained pipeline momentum.
Speaker #3: 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 this disease firsthand.
Speaker #3: It is my pleasure to introduce Dr. Ryan Darby, Associate Professor of Neurology and Director of the Frontal Temporal Dementia Clinic at Vanderbilt University Medical Center.
Speaker #3: Dr. Darby brings deep clinical expertise in frontal temporal dementia and will speak to the urgent unmet need in this disease. Dr. Darby received his undergraduate degree from Princeton University in Psychology and Neuroscience.
Speaker #3: And his medical degree from Vanderbilt University. He trained in neurology at MGH and Bringham and Women Hospitals as part of the Partners Neurology Harvard Medical School program.
Speaker #3: 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.
Speaker #3: Dr. Darby thank ou for joining us today. I will now turn the call over to you.
Speaker #4: Thank you so much for the kind introduction. Today, I'll be providing an overview of frontal temporal dementia, or FTD, which is a complex and devastating group of neurodegenerative conditions that impact thousands of individuals and their families worldwide.
Speaker #4: We'll touch on its subtypes, the clinical progression, the genetic drivers like FTDGRN, 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.
Speaker #4: 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.
Speaker #4: First, we have the behavioral variants, 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.
Speaker #4: Next, there's primary progressive aphasia, or PPA, which primarily impacts language. In FTD, this is further subdivided into two main subtypes: the semantic variant, where individuals lose their understanding of word meaning, and the nonfluent variant, where speech becomes halting and effortful.
Speaker #4: Finally, we have FTD that presents with motor or movement-related symptoms. This can present with overlapping conditions such as progressive supranuclear palsy (PSP), cortical basal syndrome (CBS), or amyotrophic lateral sclerosis (ALS) FTD, which combines features of motor neuron disease with FTD.
Speaker #4: 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 palsy, or and Tau.
Speaker #4: 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 post-mortem examination.
Speaker #4: FTD itself is more rare than Alzheimer's, but is still the most common cause of dementia in individuals under the of 60. In the US, 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 US.
Speaker #4: 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.
Speaker #4: 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.
Speaker #4: Approximately 30% of FTD cases have a strong family history. And we now recommend that there are three main autosomal dominant genetic mutations in FTD.
Speaker #4: The C9ORC72 mutation, the MAPT mutation, and the GRN mutation. There's at least 20 other rare mutations that also known to be associated with FTD.
Speaker #4: Today, we're focusing on FTDGRN, which represents about 5 to 10% of FTD cases. And this is a form that results from mutations in the GRN gene leading to a reduced level of progranulin, a critical protein for neuronal survival and function.
Speaker #4: 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 MRI are helping us to track disease progression and onset of neuronal loss more objectively.
Speaker #4: Unfortunately, there are no FDA-approved disease-modifying treatments for FTD. Management currently is largely symptomatic and supportive, often involving behavioral strategies, speech therapy, and medications targeting mood or agitation.
Speaker #4: However, there is hope on the horizon. With ongoing clinical trials now targeting genetic forms FTD, including GRN mutations, this offers an exciting opportunity to address the disease at the molecular level and develop new therapies.
Speaker #4: However, we face several key challenges. First is the diagnostic complexity. FTD is frequently misdiagnosed or diagnosed late in the disease course. Genetic testing is not routinely performed, and even in younger patients, often lack information about the underlying protein pathology making it difficult to tailor interventions or enroll appropriate patients in linical trials.
Speaker #4: 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.
Speaker #4: We need better tools to identify patients earlier in that disease course and better ways of tracking that disease over time. Finally, there's an urgent need disease-modifying therapies.
Speaker #4: Especially in 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.
Speaker #4: So in closing, FTD is a complex and deeply impactful disease both biologically and also personally for the patients and families. With increased understanding the genetic underpinnings like GRN mutation, and the development of robust biomarkers, we're in the position to truly develop transformative therapies.
Speaker #4: So with that, I'll turn the call over to Giacomo Salvadore, Elector's Chief Medical Officer.
Speaker #3: Thank you, Dr. Darby, for that insightful overview of the clinical realities and urgent unmet need in frontal temporal dementia. Your perspective helps frame the importance of our work as we approach the in-front three data readout by mid-Q4.
Speaker #3: As Dr. Darby noted, FTDGRN accounts for approximately 5 to 10% of all FTD cases. This represents about 8,000 to 17,000 cases in the US and EU alone.
Speaker #3: It is striking how many people live living with FTD still have no approved treatment options today. Underscoring the need for continued innovation and urgency in this field.
Speaker #3: 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 III in-front III trial is structured.
Speaker #3: Latozinumab 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 FTDGRN.
Speaker #3: We have evaluated Latozinumab 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.
Speaker #3: Our open-label Phase II in-front II study enrolled 12 participants with symptomatic FTDGRN. Treatment with Latozinumab normalized plasma and CSF progranulin levels. Resulting in a 2 to 3-fold increase that was rapid and sustained over the course of treatment.
Speaker #3: We also assessed a panel of disease-relevant biomarkers. Including neurofilament light chain NFL, glial fibrillary aphetic protein GFAP, and markers of lysosomal function and neuroinflammation.
Speaker #3: These biomarkers moved in the direction consistent with lowering disease progression. On the clinical side, we used the CDR Plus-Nach FTLD-SB, a validated scale for FTD that captures cognitive, functional, behavioral, and language changes.
Speaker #3: In a blinded propensity match comparison to participants from the Gen V2 natural history study, treatment with Latozinumab was associated with a 48% lowing of disease progression over 12 months.
Speaker #3: These are the same clinical measures and core biomarkers being carried forward into in-front III. Our ongoing pivotal Phase III trial. In-front III is a 96 weeks randomized double-blind placebo-controlled global trial.
Speaker #3: Evaluating Latozinumab in 103 symptomatic and 16 at-risk individuals with confirmed GRN mutations. Participants received 60 milligrams per kilogram of Latozinumab or placebo. Via intravenous infusion every four weeks.
Speaker #3: 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 plasnac FTLD thermal boxes.
Speaker #3: Following engagement with the FDA, and in line with the agency's recommendation, we and GSK have made the decision to amend the statistical analysis plan for in-front III.
Speaker #3: To include plasma progranulin as a co-primary endpoint. Along with the CDR plasnac FTLD-SB. Keep in mind that an approximate 50% reduction in progranulin is a causal factor for FTDGRN.
Speaker #3: Additionally, we are collecting fluid and imaging biomarkers. Including plasma NFL, GFAP, and volumetric MRI. We believe this positions us to deliver a clear and well-aligned data package later this year.
Speaker #3: In-front III is approximately 90% powered to detect a 40% lowing of disease progression. If our key design assumptions hold, a 25% lowing is expected to be statistically significant.
Speaker #3: And we believe that will represent a meaningful clinical benefit in a disease with no approved treatment. Latozinumab has been generally well tolerated across our clinical trials.
Speaker #3: With no major safety signal observed to date, in either healthy volunteers or patients with FTDGRN. As a reminder, Latozinumab has received breakthrough therapy and fast-track designations from the FDA.
Speaker #3: Endorphin drug designation from both the FDA and the EMA. Following a receipt of the breakthrough therapy designation, which was granted based on our Phase II data, we had a Type B interaction with the FDA.
Speaker #3: To address key elements of a potential future biologic licensing application. The agency indicated that the totality of the evidence, including clinical outcomes and disease-relevant biomarkers, could support a submission for full approval.
Speaker #3: Pending VLA 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 VLA and MAA submissions in 2026.
Speaker #3: Seeking full approval based on the strength of our trial design. Latozinumab represents a biomarker-driven, mechanistically targeted approach to treating genetically defined FTDGRN. A severe neurodegenerative disease with no approved therapies.
Speaker #3: We believe the strength of our linical data the alignment with regulators and the breadth of our clinical and biomarker package position us well as we prepare for the in-front III readout by mid-Q4.
Speaker #3: Let me also briefly comment on AL101, our second progranulin-elevating monoclonal antibody. AL101 is a distinct molecule that targets a different epitope on serolin and has a different pharmacokinetic and pharmacodynamic profile.
Speaker #3: 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.
Speaker #3: Reduced GRN expression has been implicated in Alzheimer's pathophysiology. Supporting the potential of progranulin modulation in that setting. AL101 is currently being evaluated in early Alzheimer's disease.
Speaker #3: With enrollment in the global Phase II progress A/B 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.
Speaker #2: 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.
Speaker #2: In parallel, we are advancing a research and preclinical pipeline that reflects Elector's long-term vision. These programs are grounded in the same principles that define our clinical portfolio.
Speaker #2: A strong genetic and biological rationale and high transformational potential and a focus on serious neurodegenerative diseases with first and best-in-class therapeutic approaches. A key enabler of our preclinical and research programs is our proprietary Elector brain carrier.
Speaker #2: 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.
Speaker #2: These include antibodies proteins, enzymes, and SIRNA. By selectively applying the ABC platform to drug cargoes, 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.
Speaker #2: 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.
Speaker #2: These approved antibodies have delivered plaque clearance, but only modest clinical benefit, and they are associated with side effects such as amyloid-related imaging abnormalities, or ARIA.
Speaker #2: 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.
Speaker #2: 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.
Speaker #2: 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.
Speaker #2: 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.
Speaker #2: 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.
Speaker #2: While enzyme replacement therapies are approved for peripheral manifestations of Gaucher disease, these therapies do not cross the blood-brain barrier and therefore have limited impact on neurological symptoms.
Speaker #2: 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.
Speaker #2: 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.
Speaker #2: These include a brain penetrant Tau-targeting antibody, a brain penetrant anti-Tau SIRNA, and Arelion modulator. With that, I'll turn the call over to Neil to provide an update on our financials.
Speaker #1: 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.
Speaker #1: We closed the quarter with $377.3 million in cash, which we continue to expect will provide runway into the second half of 2027. We have updated our 2025 financial guidance.
Speaker #1: 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.
Speaker #1: 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.
Speaker #1: 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.
Speaker #4: Thank you. At this time, we will conduct the question and answer session. As a reminder, to ask a question, you will need to press *11 on our telephone and wait for your name to be announced.
Speaker #4: To withdraw your question, please press *11 again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Tom Schrader of BTIG.
Speaker #4: Your line is now open.
Speaker #5: Hi, good afternoon. Thanks for taking the questions. 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?
Speaker #5: And just give us a sense of why you added that. Did progranulin, I mean, on average, it normalized, but did it normalize, does it normalize in every patient in your prior trials?
Speaker #5: I'm just trying to understand why you're doing this. And then on the ABC portfolio, is it mostly transferrin receptor-based or are you using other receptors?
Speaker #5: Thank you.
Speaker #1: Yeah, thanks for your question. This is Giacomo Salvadore, the Chief Medical Officer. The change in our statistical analysis plan to include progranulin as a co-primary endpoint was reactive to a specific request by the FDA, by Statistical Reviewer by the FDA, who asked us to make this change to the statistical analysis plan and recognizing the important mechanistic role of progranulin.
Speaker #1: This is the only change made to following a specific comment by a statistical FDA reviewer. Regarding your question about the effect on progranulin, in the population of patients with FTDGRN, we have analyzed plasma progranulin in the Phase II study and we showed a 2 to 3-fold increase in progranulin after treatment with Latozinumab.
Speaker #1: Overall, the based on our Phase II data, as well as the longitudinal data from observational studies, we feel we believe that we have more than 99% power to show statistically significant effect on progranulin.
Speaker #6: Maybe I'll take the question on the ABC platform, Tom. So yes, while we are exploring other transporter-related transport vehicles, our lead program that we are talking about do depend on the transferrin-mediated
Speaker #6: process. All
Speaker #1: Okay, great. Thank you.
Speaker #3: Tom, just to just to add to you. To Giacomo, we are not aware of any case where we treated patients without drug and we didn't see elevation of progranulin.
Speaker #3: So progranulin is consistently being elevated in treated individuals, both healthy individuals and FTD mutation carriers.
Speaker #1: Okay.
Speaker #4: right. Thank you. Our next estion comes from the line of Miles Minter of William Blair. Your line is now open.
Speaker #7: Yes. Following on from Thomas's first question, why did that reviewer request plasma progranulin? Like, this is an antibody I assume it's largely proofly restricted with some minimal getting into the brain.
Speaker #7: 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 progranulin with a largely proofly restricted antibody driving that upregulation is predictive of functional benefit in a CNS disorder like frontotemporal dementia?
Speaker #7: That's Just on the background of what we've seen with the take of anti-amyloid therapies in Alzheimer's disease showing a 27% slowing of decline, I ow there's some safety concerns with that.
Speaker #7: the first one. And then if Dr. Darby's still on the line, I think in front III at its bare minimal was powered to show a 25% improvement in the slowing of cognitive decline in this trial.
Speaker #7: But if it was 25%, is that still an attractive product to prescribe to this patient population? Thank ou very much.
Speaker #1: Thank you very much for your question. So the FDA didn't provide detailed rationale for their input on the analysis plan and the rationale behind their suggested change.
Speaker #1: And elevating progranulin as a co-primary endpoint. We believe that their FDA input underlines the importance of progranulin as a biologically meaningful marker. In FTDGRN.
Speaker #1: Mutation of in progranulin gene in granulin gene lead to upload insufficiency 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 a previous calls and we had an agreement that elevation of progranulin could subserve as confirmatory evidence in our Latozinumab program.
Speaker #1: So this this fall, this change follows follows some previous discussion that we have disclosed before. Regarding your second comments on peripheral versus central, we in the Phase II study, we were able to show robust increases of progranulin 2 to 3-fold both in the CSF as well as in plasma.
Speaker #1: Therefore, our previous data indicates a strong effect no matter what the compartment is chosen to study progranulin elevation.
Speaker #3: Yes, there is a really good correlation with our drug between the serum and the CSF. Both in healthy volunteers and in patients and in both of our drugs, both in 001 and 101.
Speaker #3: So with sort of both of our drugs, the plasma progranulin appeared to be a good representation of what's actually will also happen in the CSF in the brain.
Speaker #8: Hi, this is Ryan Darby. I can answer the other questions. Now's the right time?
Speaker #1: Yes.
Speaker #8: You know, so in terms 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.
Speaker #8: I think in the anti-amyloid infusion comparison, you know, the issues with implementation there, I think center the side effects and that cost-benefit profile that we're discussing with patients where some patients would opt away from that.
Speaker #8: I think an FTD with no other viable treatment options there'd be more of an interest in that. Would obviously depend on the other side effect profile and at that looked like.
Speaker #1: Beautiful. Thanks for the questions.
Speaker #3: Yes, so far, so the our drug appears to be very well tolerated. There are no sort of meaningful drug-related adverse effects or it will be with regard to safety and different appear to be a different profile than the anti-A beta therapeutics.
Speaker #4: All right. Thank ou. Our next question comes from the line of Alex Stratahand of Bank of America. Your line is now open.
Speaker #9: Hey, guys. Thanks for taking our estions. One on AL001 from us as well. Curious how changing the SAP at this stage could affect powering on the modified CDR somat boxes since plasma PGRN is now a co-primary.
Speaker #9: And in our discussions with the FDA or and/or GSK, I'm ious if expanded enrollment in in-front III was was part of your discussions at all.
Speaker #9: 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?
Speaker #9: Thanks.
Speaker #1: Thanks for your questions. So to start, regarding our program, how the change in the SAP to include progranulin as a co-primary affects the power or affects the conduct of the study, I can tell you that with having two co-primary endpoints, one clinical, the CDR FTLD somat box and progranulin, we need to show statistically significance on both co-primary endpoints for the study to be positive.
Speaker #1: Having said that, these two co-primary endpoints are analyzed independently. Meaning that the power regarding the CDR somat boxes remain unchanged and as I said before, regarding progranulin, based on our Phase II data, we have more than 99% power to show a significant effect on elevating progranulin.
Speaker #1: Other sorry, can you repeat the other question?
Speaker #9: Yeah, just given the focus of the FDA on plasma PGRN, curious if this could be a potential. Whether
Speaker #1: Yeah, yeah.
Speaker #9: in terms of the population on the label.
Speaker #1: Yeah, we haven't had any discussions about labeling and we will entertain discussion with regulators after we have the trial readout in mid-Q4 2025. But we didn't have any discussion about progranulin being part of the label.
Speaker #9: Understood. Thank you very much.
Speaker #1: Sure.
Speaker #4: Thank you. Our next estion comes from the line of your own Werber of TD Securities. Your line is now open.
Speaker #10: And thank you very much for the estion. This is Steven Ianov on for your own Werber. Did the FDA mention any particular thresholds that they wanted to see for progranulin or is that just statistical significance?
Speaker #10: And then to follow up, you mentioned the 90% power to see a 40% lowering. Was that are you tying that in any way to the progranulin levels or is that just still the somat boxes endpoint?
Speaker #10: Thank ou.
Speaker #1: Sure. The FDA did specify any significant any particular threshold regarding the elevation of progranulin that they would want to see based on our trial data.
Speaker #1: 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 of the study's power for 40%, so we know this is progression with Latozinumab versus placebo.
Speaker #1: And this power remains unchanged after the modification. The as I mentioned just now, the CDR somat boxes and progranulin are analyzed separately. So the initial assumption regarding CDR remains unchanged and we there is no no no change you ow regarding the CDR somat boxes.
Speaker #1: And progranulin, we are 99% powered based on our Phase II data. So it doesn't so we don't think it's going to affect the probability of success overall.
Speaker #1: But the considering the fact that we in order for the study to be positive, we need to show significance on both co-primary endpoints.
Speaker #3: Yeah, just like to add again that even if we see 25% slowdown in cognitive decline this will be statistically significant, clinically meaningful, and will most likely be approvable.
Speaker #9: Understood. Thank ou very much.
Speaker #4: Thank ou. Our next question comes from the line of Sean Lohman of Morgan Stanley. Your line is now open.
Speaker #11: 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.
Speaker #11: First one for Dr. Darby. We'd love to hear your thoughts. Assuming success restoring progranulin to normal levels and FTG progranulin, like slowing CDRSB, would that increase your confidence in elevating progranulin above endogenous levels like being beneficial to patients with Alzheimer's?
Speaker #8: 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.
Speaker #8: I don't know it would move you all the way to saying that supra-normal levels would have increased benefit if I'm standing 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.
Speaker #9: 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?
Speaker #8: Yeah, I mean, I think it would it would definitely make me curious of seeing what that effect could potentially be. So that you ow if this is protective, would going even above the normal levels be helpful?
Speaker #8: I think it would open up that that 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?
Speaker #8: And then you'd be able to show that there is something that is potentially able to do that.
Speaker #9: Thank you so much. That's really helpful. And then I ess my follow-up question would be for management. For in-front III, given the potential for inner patient variability on baseline progranulin level, be it by stage disease or other factors, be it like semantic or motor disruptions, like how are ou normalizing for that?
Speaker #9: Is it like the FDA requesting like it was in-subjects comparison from baseline to the study end? Or is it more like an aggregate comparison between study arms?
Speaker #1: I can take this one. So the we are finalizing the SAP and you know enclosed discussion with the FDA and they we are going to analyze plasma progranulin change in the active arm versus placebo.
Speaker #1: So we didn't have any specific request. I can I can add the fact that upload ufficiency in the granulin gene is associated with 50% reduction of progranulin levels.
Speaker #1: And this is enough to produce a disease phenotype, meaning that 50% decrease in progranulin level are almost invariably associated with frontotemporal dementia and development of the full-blown disease.
Speaker #1: Our previous data showed 2 to 3-fold elevation of plasma progranulin and we the and yeah, also the CSF data are very consistent with that and we are were able to show normally the normalization of those levels in individuals who had at baseline deficits.
Speaker #1: So Arnon, I don't know if you want to add anything but it's we see a consistently low levels of progranulin in patients with FTDGRN.
Speaker #1: This is a functional mutation we see associated with the disease phenotype.
Speaker #3: Yes, mechanistically the mutations that cause frontotemporal dementia are full heterozygous loss of function that these are coding mutations that lead to complete ablation of the mutated protein.
Speaker #3: There's no gradation in the mutated protein. So every individual that has mutations that cause frontotemporal dementia are coding mutations that lead to upload ufficiency, like 50% or less of the progranulin.
Speaker #3: Then the promoter mutation, though actually the three prime untranslated region mutation that you referred to are a different class of mutations. These are mutations that are associated with very modest reduction in progranulin of 10 to 15% and they are associated with other diseases like Parkinson's disease and Alzheimer's disease.
Speaker #3: And but they sort of they don't lead to frontotemporal dementia.
Speaker #4: Thank you so much. That's been really helpful. I appreciate all the calling.
Speaker #9: Thank ou.
Speaker #4: Our next question comes the line of Greg Zovanovich of Mizuo. Your line is now open.
Speaker #12: Hi there. This is Doug McPherson on for Greg. Thank you very much for having me on and taking my call. Our 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 the spread or separation between active drug and placebo?
Speaker #1: 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.
Speaker #1: Regarding biomarkers, they are unlikely to show any effect any placebo effect with those are objective measures NFL as well as GFAP, embolometric MRI. There is not you know there is no placebo effect as far as we know.
Speaker #1: Regarding, broadly speaking, the placebo effects on clinical outcome measures, what we know from neurodegenerative diseases is that if placebo effects are present at all, they typically tend to manifest in the first few weeks of treatment and tend to dissipate over time.
Speaker #1: Our trial are the in-front III studies 96 weeks long and in a disease that show progression over time. So we don't see the placebo effect as a particular risk for this kind of indication.
Speaker #9: Sure. Thank you for that. preciate 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?
Speaker #1: Yeah, you're asking about which program in ?
Speaker #9: Oh, I'm still on the FTD Phase III study.
Speaker #1: So we are monitoring blind safety periodically and you know there is an independent and then I monitoring committee which oversees the safety of the drug.
Speaker #1: As well and we didn't have reports of ARIA in with them in the study AS in-front III.
Speaker #9: Oh, that's great to hear. Thank ou so much.
Speaker #1: 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 amyloid from the brain, especially from the vasculature.
Speaker #1: So in the absence of amyloid or when it is not a prominent feature of the disease, I think the biological rationale for underlying the artificial physiology is not present.
Speaker #1: Just wanted to clarify this. So that's why it's not not expected as a feature of this treatment and you know we haven't observed it you ow.
Speaker #1: So far.
Speaker #9: That's at to hear. Thank you very much. I appreciate you taking the estion.
Speaker #1: Sure.
Speaker #4: Thank ou. Our next question comes from the line of Paul Mateus of STIFL. Your line is now open.
Speaker #10: Hi, this is Emily on for 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?
Speaker #10: How would you feel about your chances at approval in that situation thanks?
Speaker #1: Sure. Thanks for the question. So the study in-front III is enrolled 103 subjects with symptomatic FTDGRN. We collect a number of clinical measures as well as biomarkers and we will be if the data supported we will be pursuing full approval.
Speaker #1: Based on the data, and given the fact that there is there are no approved treatments and there is a disease with a very huge burden as Dr. Darby reminded us, just earlier, we if they 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 progranulin.
Speaker #1: We but again, we are we are meant to pursue full approval if the data supports it. And what we know from the CNS space, the FDA, as recently approved drugs with based on biomarker findings, if we think about the approval of Tophers and in SOD1 ALS.
Speaker #1: So there are regulatory precedents, especially in CNS diseases which are rare and where with no approved treatment options. But we are pursuing full approval if the data supports .
Speaker #10: Thanks. And then just one follow-up. Were you able in that meeting with the FDA to confirm your sample confirm alignment on the sample size again?
Speaker #10: Thank you.
Speaker #1: 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 a blind sample size reestimation and we observed the lower variability on the primary outcome measure, the CDR somat boxes FTLD.
Speaker #1: As we we had in mind in our original powering assumption. So we agreed with the FDA the sample size within 90 and 100 subjects would be sufficient to show 40% slowing of disease progression in the active arm with Latozinumab versus placebo.
Speaker #1: And we we got an agreement with them on the sample size and then we enrolled 103 subjects. So over slightly over the number that we think it's needed to show a clinical effect.
Speaker #10: Thanks.
Speaker #4: Thank you. Our next question comes from the line of Pete Stavropulos of Cantor Fitzgerald. Your line is now open.
Speaker #10: Hi, this is Samantha Schafer on the line for Pete. Thanks so much for taking our question. So a question for the team Dr. Salvadore, Dr. Darby related to in-front III.
Speaker #10: 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 you expect signs of progression and potential differences between Latozi and placebo within the 96 weeks?
Speaker #10: And then I just have a follow-up question. Thank you.
Speaker #1: Sure. Thanks for the question. So as you currently said, the primary population is our patients who are symptomatic. So these 103 subjects that I just mentioned.
Speaker #1: Asymptomatic subjects, 16 of them were enrolled in the trial and will be part of sensitivity analysis. The study is ongoing. It remains blinded. 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.
Speaker #1: We will definitely look at the data and part of sensitivity analysis and possibly entertain discussions with the regulators, based on on the data that we observe.
Speaker #1: On the results that we observe.
Speaker #3: Just to add to this, the recruitment of the pre-symptomatic patients, as you said, based on genetic mutations or frontotemporal 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.
Speaker #3: 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 neurofilament.
Speaker #10: That's very helpful. Thank you. And just to follow up, we know that there's a part two of the in-front study on it's open-label extension.
Speaker #10: 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?
Speaker #1: 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-label extension and we think that they 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 placebo to active treatment.
Speaker #1: Moving to the open-label extension. There are some very esting and meaningful precedents in the CNS space about how this open-label extension data can provide more clarity on the meaningfulness of the results from the double-blind portion of the study.
Speaker #1: So we we are you ow we remain interested in looking at the at the results. But again, the the statistical I mean, the the analysis will be focused on part one, which is the double-blind portion of the study, 96 weeks.
Speaker #1: So we will not you know we will not focus on the on the open-label extension for now.
Speaker #10: Great. Thank you guys so much.
Speaker #1: Sure.
Speaker #4: Thank ou. I'm showing no further questions at this time. I would now like to turn it back to Neil Berkeley for closing remarks.
Speaker #12: Thank you. Before we end the conference call, I'd like to share that Alector will be participating in a number of upcoming conferences, including the 2025 Cantor Global Healthcare Conference on September 4th in New York.
Speaker #12: The Morgan Stanley 23rd Annual Global Healthcare Conference on September 8th in New York. And the HC Wainwright 27th Annual Global Investment Conference on September 9th in New York.
Speaker #12: Thank you again for your time and attention. We will now conclude today's call.
Hm.