Q4 2024 Alector Inc Earnings Call
<unk> 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 star one on your telephone you wouldn't hear an automatic automated message advising your hand to raise too.
Speaker Change: To withdraw your question. Please press Star one again as a reminder, this conference 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.
Operator: Good afternoon, ladies and gentlemen, and welcome to Elektor fourth quarter and full year 2024 earnings conference call. At this time, all participants are in a listen only mode.
Katie Hogan: Thank you operator, and Hello, everyone earlier. This afternoon, we released our financial results for the fourth quarter and full year 'twenty 'twenty four.
Operator: After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you would need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again.
Katie Hogan: The press release is available on our website at www dot elect their dot com and our 10-K was filed with the Securities and Exchange Commission. This afternoon joining.
Operator: As a reminder, this conference is being recorded.
Katie Hogan: Joining me on the call today are Dr. Arnon Rosenthal co founder and CEO, Dr. Sarah can carry Mitra, President and head of research and development.
Katie Hogan: 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 fourth quarter and full year 2024. The press release is available on our website at www.elector.com and our 10k was filed with the Securities and Exchange Commission this afternoon.
Katie Hogan: Gary Romano, Chief Medical Officer, and Dr. Marc Grasso, Chief Financial Officer.
Katie Hogan: After her for him over remarks, we'll open the call for Q&A.
Speaker Change: 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.
Speaker Change: I would now like to turn the call over to Arnon Rosenthal, Chief Executive Officer Arnon.
Katie Hogan: Joining me on the call today are Dr. Arnon Rosenthal, co-founder and CEO, Dr. Sara Kenkare-Mitra, President and Head of Research and Development, Dr. Gary Romano, Chief Medical Officer, and Dr. Marc Grasso, Chief Financial Officer. 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.
Speaker Change: Thank you Katie good afternoon, everyone and thank you for joining alecto fourth quarter and full year granted patent before finance results conference call.
Speaker Change: I'd like to begin by archiving.
Speaker Change: Direction guiding electro fold.
Speaker Change: The opportunities that lie ahead.
Speaker Change: We are focused on discovering and developing first or best in class disease modifying therapies for no. Other general all do such as Frontotemporal dementia, Alzheimers disease and Parkinson's disease.
Arnon Rosenthal: I would now like to turn the call over to Arnon Rosenthal, Chief Executive Officer. Arnon? Thank you, Katie. Good afternoon, everyone. And thank you for joining Alector's first quarter and full year 2024 Financial Results Conference call.
Speaker Change: With high unmet medical need.
Speaker Change: Our effective medicines.
Speaker Change: Gently required.
Speaker Change: To achieve this we continue to build an integrated biotechnology organization that combines deep expertise in genetics immunology and neuroscience.
Arnon Rosenthal: I'd like to begin by outlining our strategic direction guiding Elector 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 capabilities. We pursue therapies that target the 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 programs developed in collaboration with GSK.
Speaker Change: With extensive drug discovery protein engineering and manufacturing.
Speaker Change: As well as clinical development and regulatory capabilities.
Speaker Change: We pursued therapies that target the underlying mechanisms of neuro degeneration, such as toxic misfolded protein deficient proteins and the function in immune lysosomal neuronal systems.
Speaker Change: Our portfolio includes two first in class late stage clinical program developed in collaboration with GSK.
Speaker Change: Along with five discovery programs encompassing antibodies enzymes and nucleic acids.
Speaker Change: Addressing both novel and more established targets.
Central to our program is alecto, Brian carrier.
Speaker Change: <unk>, our proprietary and versatile blood brain barrier platform.
Speaker Change: ABC same store enhance the delivery of our protein and nucleic acid therapeutics to the brain to improve efficacy and increase safety at lower those costs.
Speaker Change: Sure.
Speaker Change: We are advancing our wholly owned ABC based programs.
Arnon Rosenthal: along with five discovery programs encompassing antibodies, enzymes, and nucleic acids. addressing both novel and more established targets.
Speaker Change: We expect to bring the clearly 2026.
Speaker Change: We anticipate realizing a significant portion of the company's potential in 2025.
Arnon Rosenthal: Central to our program is Alecto Brain Carrier or ABC, our proprietary and versatile blood-brain-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 2020. We anticipate realizing a significant portion of the company's potential in 2025. The readout of our Pivotal Phase III trial in frontotemporal dimension with progranulin gene mutation is planned for later this year. Additionally, we expect to complete patient recruitment for PROGRESS-AD, our Phase 2 trial of AL-101 in early Alzheimer's disease.
Speaker Change: The readout of our pivotal phase III trial in Frontotemporal dementia with Borgwarner language and rotation is planned for later this year.
Speaker Change: Additionally, we expect to complete patient recruitment for breath say.
Speaker Change: Although our phase II trial of Am 101 in early Alzheimer's disease.
Speaker Change: Beyond these initiatives. We are also advancing our preclinical pipeline with Sarah will discuss later today.
Speaker Change: Throughout this process, we remain committed to making data driven decisions that create sustainable value.
Speaker Change: With that I'll turn the call over to Gary to discuss our goals and expectations for our clinical development programs.
Speaker Change: Gary.
Gary Romano: Thank you arent on I'll begin with <unk> our novel first in class for granular elevating candidate, which we are developing in partnership with GSK.
Arnon Rosenthal: Beyond these initiatives, we are also advancing our preclinical pipeline, which Sara will discuss later today. Throughout this process, we remain committed to making data-driven decisions that create sustainable value.
It is the most advanced therapeutic candidates in clinical development for the treatment of frontal temporal dementia in patients with a granular mutation or STD granular.
<unk> is a rare neurodegenerative disease, but it is one of the most common causes of early onset dementia.
Gary Romano: With that, I'll turn the call over to Gary to discuss our goals and expectations for our clinical development programs. Gary. Thank you, Arnon. I'll begin with Lata Sinemab, our novel first in class for granular and elevating candidate, which we are developing in partnership with GS. It is the most advanced therapeutic candidate in clinical development for the treatment of frontotemporal dementia in patients with a granulone mutation or FTD granuloma. FDD 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.
Gary Romano: Currently there are no approved treatment options available for patients with FCB.
Gary Romano: Heterozygous loss of function mutations in the granular gene results in Harpoon sufficiency of pre granular, reducing CNS levels to 50% of normal and our causal for FTE with penetrance that approximates a 100%.
Gary Romano: Madison, Nevada is a novel investigational human monoclonal antibody designed to block and down regulate the <unk> receptor, which is one of several receptors that take up for granular and from the extra cellular space.
Gary Romano: <unk> results in an increase in extra cellular programming, one, but <unk> has been evaluated in phase one and phase II trials with ongoing evaluation in a pivotal phase III trial for which top line data is expected by the fourth quarter.
Gary Romano: Heterozygous loss of function mutations in the granulone gene results in haploinsufficiency of progranulone. Reducing CNS levels to 50% of normal and are causal for FTD with penetrance that approximates 100%. Laticinimab is a novel investigational human monoclonal antibody designed to block and downregulate the sirtulin receptor. which is one of several receptors that take up progranulin from the extracellular space. This blockade results in an increase in extracellular programmulon. Latazinamab has been evaluated in Phase 1 and Phase 2 trials with ongoing evaluation in a pivotal Phase 3 trial for which top line data is expected by the fourth quarter.
Gary Romano: He had front two phase II open label study evaluated treatment effects of <unk> and 12 subjects with symptomatic FTB granular.
Gary Romano: Effects on <unk> levels of Biomarkers of license almost function inflammation, astrogliosis and neuro degeneration were assessed after 12 months of treatment.
Gary Romano: Treatment restored for granular to normal levels in both plasma and CSF, representing a two to three fold increase which was rapid and sustained over the treatment duration of 49 weeks.
Gary Romano: Although the number of participants in this cohort was relatively small all the biomarker data moved in a direction that we would expect if gladys <unk> slows the progression of FTE pathophysiology.
Gary Romano: The In Front 2 Phase 2 Open Label Study evaluated treatment effects of laticinimab in 12 subjects with symptomatic FTD granuloma. effects on progranulin levels and biomarkers of lysosomal function, inflammation, astrogliosis, and neurodegeneration were assessed after 12 months of treatment. Treatment restored progranulin to normal levels in both plasma and CSF, representing a two to three-fold increase, which was rapid and sustained over the treatment duration of 49 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 lattice NMAD slows the progression of FTD pathophysiology.
Gary Romano: To determine whether there was a treatment related slowing of disease progression, we assess change on the CVR plus snack ftl's summer boxes, which is an SPD 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 <unk>.
Gary Romano: Point in our pivotal phase III trial, we conducted a blinded comparison of disease progression rates between the <unk> treated participants in front too so baseline propensity matched participants from the Gen <unk> observational study.
Gary Romano: This analysis demonstrated that clinical disease progression and the latest <unk> treated subjects was slowed by 48% over one year compared to the Genesee subjects.
Gary Romano: To determine whether there was a treatment-related slowing of disease progression, we assessed change on the CDR plus NAC 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 3 trial. We conducted a blinded comparison of disease progression rates between the laticinimab-treated participants in INFRONT2 to baseline propensity-matched participants from the GENPHY-2 observational study. This analysis demonstrated that clinical disease progression in the laticinimab-treated subjects was slowed by 48% over one year compared to the Gen-P subjects.
Speaker Change: In <unk> as a pivotal phase III randomized double blind placebo controlled trial with a treatment duration of 96 weeks. The trial enrolled 103, symptomatic and 16 at risk FTB granular participants who were randomized to receive either 60 milligrams per kilogram of <unk> intravenously.
Gary Romano: Every four weeks or placebo and <unk>.
Gary Romano: Accordingly in this phase III study, we are collecting the same clinical outcome assessments and biomarkers that we assessed in the phase II study of letters sent them out.
Gary Romano: Previously we gained alignment from the FDA and EMA to conduct the primary analysis on symptomatic participants in <unk> III.
Gary Romano: In front three is a pivotal phase three randomized double blind placebo controlled trial with a treatment duration of 96. The trial enrolled 103 symptomatic and 16 at-risk FTD-granulone participants. who were randomized to receive either 60 milligrams per kilogram of laticinimab intravenously every four weeks or placebo. Importantly, in this Phase 3 study, we are collecting the same clinical outcome assessments and biomarkers that we assessed in the Phase 2 study of lidocinema. Previously, we gained alignment from the FDA and EMA to conduct the primary analysis on symptomatic participants in In Front 3. We intend to include the at-risk participants in sensitivity analysis.
Gary Romano: We intend to include the at risk participants and sensitivity analysis.
Gary Romano: In February 2020 for FCA granted lettuce in the Mab.
Gary Romano: Breakthrough therapy designation for FTE granular based on our in front two phase III clinical trial data.
Gary Romano: With this designation last year, we held a type D interaction with FDA on the potential future biologics license application provided cinema.
The FDA indicated that it would consider the effects of <unk> on plasma and CSF for granular levels as confirmatory evidence supplementing the potential clinical effects of <unk> pending BLA review.
Gary Romano: We also aligned with the agency on disease relevant fluid and imaging biomarkers that may be considered as supportive evidence of clinical efficacy.
Gary Romano: In February 2024, FDA granted laticinimab breakthrough therapy designation for FTD granulin based on our InFront2 Phase 2 clinical trial data. With this designation, last year we held a Type B interaction with FDA on the potential future biologics license application for laticinimab. The FDA indicated that it would consider the effects of laticinimab on plasma and CSF pergranulin levels as confirmatory evidence. supplementing the potential clinical effects of latazinamab 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.
Gary Romano: So subject to BLA review.
Gary Romano: 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 provided cinema.
Gary Romano: In September of 2024, we presented the patient baseline characteristics for infra III at the 14th International conference on frontal temporal dementia or <unk> 2020 for the baseline characteristics of symptomatic participants, including age Ctr snack <unk> silver boxes scores.
Gary Romano: And if NFL levels were representative of the broader FTE granular registry population.
Gary Romano: 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 lattice enema.
Gary Romano: Based on available registry data.
Gary Romano: <unk> is designed to provide approximately 90% power to detect a 40% slowing of disease progression.
Gary Romano: In September of 2024, we presented the patient baseline characteristics for InFront3 at the 14th International Conference on Frontotemporal Dementias, or ISFTD 2020. The Baseline Characteristics of Symptomatic Partitioning. Recruiting age, CDR, plus NAC FTLD sum of boxes scores, and NFL levels were representative of the broader FDE Granulone Registry population. based on available registry data. InFront3 is designed to provide approximately 90% power to detect a 40% slowing of disease. If our trial design assumptions hold a 25% slowing of disease progression, it's expected to be statistically significant.
Gary Romano: If our trial design assumptions hold a 25% slowing of disease progression is expected to be statistically significant.
Gary Romano: I'd like to now turn to <unk> hundred one our second product candidate in our per granular portfolio that we are developing in partnership with GSK.
Gary Romano: <unk> <unk> hundred one is a monoclonal antibody designed to block it down regulate the <unk> receptor to elevate the level of pre granular 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 <unk>.
Gary Romano: <unk> disease.
Gary Romano: Our phase one study in healthy volunteers demonstrated that <unk> hundred one was well tolerated and increased <unk> levels in plasma and CSF in a dose dependent manner.
Gary Romano: I'd like to now turn to AL101, our second product candidate in our Progranulin portfolio that we are developing in partnership with GSK. Y-clenicinimab, AL-101, is a monoclonal antibody designed to block and down-regulate the sirtulin receptor to elevate the level of progranulin in the brain. These 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. Our phase one study in healthy volunteers demonstrated that AL-101 was well tolerated and increased programming levels in plasma and CSF in a dose-dependent manner.
Gary Romano: The ongoing progress <unk> phase II trial available 101, operationalized by our partner GSK is enrolling approximately 282 participants with early Alzheimer's disease across multiple global sites with enrollment expected to complete by mid 2025.
Gary Romano: The first participate with dose just one year ago in February 2024.
Gary Romano: Progress is a 76 week randomized double blind placebo controlled clinical trial of <unk> 101, designed to assess the safety and efficacy of two doses of <unk> hundred one compared to placebo.
Gary Romano: The ongoing PROGRESS-AD Phase 2 trial of AL-101, operationalized by our partner GSK, is enrolling approximately 282 participants with early Alzheimer's disease across multiple global sites, with enrollment expected to complete by mid-2025. The first participant was dosed just one year ago, in February 2024. Progress AD is a 76-week, randomized, double-blind, placebo-controlled clinical trial of AL-101 designed to assess the safety and efficacy of two doses of AL-101 compared to placebo. The primary endpoint of the study is disease progression as measured by the clinical dementia ratings from a box. The trial also employs other clinical and functional outcome assessments and biomarkers.
Gary Romano: The primary endpoint of the study is disease progression as measured by the clinical dementia ratings from our boxes.
Gary Romano: Trial also employs other clinical and functional outcome assessments and Biomarkers, we look forward to sharing additional information on proper safety as the trial advances.
Gary Romano: Finally on April 5th we plan to present the results from the invoke two phase III clinical trial, which evaluated the safety and efficacy of <unk> <unk> to a <unk> agonist and individuals with early Alzheimer's disease.
Gary Romano: Results will be delivered during an oral presentation at <unk> 2025 International conference on Alzheimer's and Parkinson's disease, taking place in Vienna, Austria.
Gary Romano: We remain committed to advancing the understanding of Alzheimer's pathophysiology and the development of effective therapeutics for the disease.
Gary Romano: We look forward to sharing additional information on PROGRESS-AD as the trial advances.
Gary Romano: With that I'll now turn the call over to Sarah to provide an update on our preclinical pipeline Sara.
Gary Romano: Finally, on April 5th, we plan to present the results from the INVOKE-2 Phase II Clinical Trial, which evaluated the safety and efficacy of AL002, a TREM-2 agonist in individuals with early Alzheimer's.
Sarah Mitra: Thank you Danny.
Sarah Mitra: I'm, making swift and steady progress in advancing our electro pain carrier and a preclinical and research pipeline with strong momentum across several key program.
Gary Romano: Results will be delivered during an oral presentation at the ADPD 2025 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.
Sarah Mitra: As R&R noted our strategy focuses on developing product candidates that remove toxic proteins replace clinical deficient protein.
Sarah Mitra: And restore immune and nerve function.
Sarah Mitra: Sue this aimed at advancing our portfolio of programs that address novel and established target.
Sara Kenkare: With that, I'll now turn the call over to Sara to provide an update on our pre-clinical pipeline. Sara? Thank you, Gary. We are making swift and steady progress in advancing our electro-brain carrier and our preclinical and research pipelines with strong momentum across several key programs. As Arnon noted, our strategy focuses on developing product candidates that remove toxic products replace critical deficient and Restore Immune and Nerve Cells 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 transmission.
Sarah Mitra: These programs leverage our deep understanding of the genetic underpinning of neuro degenerative diseases combined with our expertise in drug discovery and our proprietary ADC technology for Black Bean day in transport.
Sarah Mitra: At the lector, we've worked hard over several years to realize the potential of our proprietary electronic based carrier technology platform.
Sarah Mitra: The ADC platform enables the targeted delivery of therapeutics to the brain.
Sarah Mitra: We believe that it is 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.
Sarah Mitra: We have applied our ADC technology to multiple therapeutic carloads.
Sarah Mitra: Our ADC platform targets receptors that I expressed on the black bend area using receptor mediated translate to answers to enable the efficient delivery of therapeutic across the blood brain barrier and ensuring that targeted action within the current guidance.
Sara Kenkare: At Alector, we've worked hard over several years to realize the potential of our proprietary electrode brain carrier technology platform. Our ABC platform enables the targeted delivery of therapeutics to the 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 products. 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 parent.
Sarah Mitra: Our ADC technology is used in several of our preclinical program, including a candidate that replaces cheeky.
Sarah Mitra: And Ah candidates that target, unlike beta and Tau pathology.
Sarah Mitra: Adp's <unk> 700, ADC in our proprietary anti amyloid beta antibody fragment ADC for the treatment of Alzheimers disease.
Sarah Mitra: By leveraging ADC technology, Adp's <unk> seven ADC play aimed to clear analyzed data efficiently, thereby reducing plaque accumulation and slowing disease progression, while minimizing the risk of ARIA.
Sara Kenkare: Our ABC technology is used in several of our preclinical programs, including our candidate that replaces and our candidates that target amyloid beta and telcethol. ADB 0378 is a proprietary anti-amyloid beta antibody paired with ABC for the treatment of Alzheimer's. By leveraging ABC technology, ADP037-ABC aims to clear amyloid beta efficiently, thereby reducing plaque accumulation and slowing disease progression while minimizing the risk of heart attack. It targets a validated epitope specific to brain amyloid beta plaques combined with an optimized antibody constant region to enhance phagocytosis of amyloid beta. In Parkinson's disease, we are advancing ADP050ABC, a GK replacement therapy for GBA gene mutation carriers with Parkinson's.
Sarah Mitra: It targets, a validated epitope specific to brain amyloid beta plaque combined with an optimized antibody constant region to enhance phagocytosis analyzed data plugs.
Sarah Mitra: In Parkinson's disease, we are advancing Adp's 050, ADC, a GK replacement therapy for GBA gene mutation carriers with Parkinson's disease.
Sarah Mitra: And these patients GBA mutations lead to deficient gk's activity.
Speaker Change: <unk> ADC uses an electrical engineer in Chongqing, which is proprietary and has been designed to be more stable and active.
Speaker Change: ADP 050, ADC aimed to prevent the accumulation of toxic brain single lipid that contribute to new in each generation.
Speaker Change: Dressing this mechanism our goal is to reduce cellular dysfunction and slow disease progression.
Speaker Change: We are currently selecting lead candidates for both our anti amyloid beta and GKN program and we are on track to advance them towards IND, enabling studies this year.
Sara Kenkare: In these patients, GBA mutations lead to deficient GKs activity. ADP 050-ABC uses an electro-engineered GKs which is proprietary and has been designed to be more stable and accurate. ADP050-ABC 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.
Speaker Change: We are also developing two at <unk> targeting program that each take a distinctive approach to tackling tau pathology for the treatment of Alzheimer's disease.
Speaker Change: One program focuses on using an anti tau antibody, while the other focuses on using an anti tau anti R&D.
Speaker Change: In addition, we are also advancing our reading modulator designed to block Tau pathology and promotes synaptic function for the treatment of Alzheimer's disease.
Sara Kenkare: We are currently selecting lead candidates for both our anti-amyloid beta and GKs programs, and we are on track to advance them towards IND-A Daping Studies this year.
Speaker Change: Lastly in collaboration with the University of Luxembourg, Electrical was awarded a $1 7 million grant from the Michael J Fox Foundation for Parkinson's as such.
Sara Kenkare: We are also developing two TAO targeting programs that each take a distinctive approach to tackling TAO pathology for the treatment of Alzheimer's. One program focuses on using an anti-tau antibody, while the other focuses on using an anti-tau SIR. In addition, we are also advancing a Riehlian modulator designed to block tau pathology and promote synaptic function for the treatment of Alzheimer's.
Speaker Change: This funding will support our research on GP NMD, a promising target for Parkinson's disease.
Speaker Change: Looking ahead, we plan to hold a virtual educational event in the second quarter of 2025 to share additional preclinical data on our anti amyloid beta ngk's programs as well as other advancements in our ADC platform.
Speaker Change: With that I'll now turn it over to Mark to provide an update on our financial results Tomorrow.
Sara Kenkare: Lastly, in collaboration with the University of Luxembourg, Alector was awarded a $1.7 million grant from the Michael J. Fox Foundation for Clark. This funding will support our research on GPNMV, a promising target for Parkinson's.
Mark: Thank you Sarah as summarized in our fourth quarter and full year 2024 financial results, which we made available after the market closed today, we are in a strong cash position to deliver against our strategic objectives.
Mark: We continue to focus on fiscal management and program prioritization and as of December 31, 2024, our cash cash equivalents and short term investments totaled $413 4 million.
Sara Kenkare: Looking ahead, we plan to hold a virtual educational event in the second quarter of 2025 to share additional preclinical data on our anti-amyloid beta and GKs programs, as well as other advancements in our ABC platform.
Mark: Now turning to our operating results.
Marc Grasso: With that, I'll now turn it over to Marc to provide an update on our financial results. Thank you, Sara. As summarized in our fourth quarter and full year 2024 financial results, which we made available after the market closed today, we are in a strong cash position to deliver against our strategic objectives. We continue to focus on fiscal management and program prioritization, and as of December 31st, 2024, our cash, cash equivalents, and short-term investments totaled $413.4 million.
Mark: Collaboration revenue for the fourth quarter was $54 2 million compared to $15 2 million for the same period in 2023.
Mark: Collaboration revenue for the year was $106 million.
Mark: Compared to $97 1 million in 2023.
Mark: Total research and development expenses for the fourth quarter were $46 5 million.
Mark: Compared to $47 7 million for the same period in 2023.
Mark: Total research and development expenses for the year were $185 9 million.
Marc Grasso: Now, turning to our operating results. Collaboration revenue for the fourth quarter was $54.2 million, compared to $15.2 million for the same period in 2023. Collaboration revenue for the year was $100.6 million compared to $97.1 million in 2023. Total research and development expenses for the fourth quarter were $46.5 million. compared to $47.7 million for the same period in 2023. Total research and development expenses for the year were $185.9 million compared to $192.1 million in 2020. Total general and administrative expenses for the quarter were $15 million compared to $14.9 million for the same period in 2020. Total general and administrative expenses for the year were $59.6 million compared to $56.7 million in 2020.
Mark: Compared to $192 1 million in 2023.
Total general and administrative expenses for the quarter were $15 million compared to $14 9 million for the same period in 2023.
Mark: Total general and administrative expenses for the year were $59 6 million compared to $56 7 million in 2023.
Mark: For 2025, we estimate our collaboration revenue to be between five and $15 million.
Mark: Our anticipated total research and development expenses are estimated to be between 175 and $185 million.
Mark: And total general and administrative expenses are estimated to be between $55 65 billion.
Mark: We remain focused on advancing our broad and diverse portfolio as well as our electric <unk> technology to treat neurodegenerative diseases. We.
Mark: We look forward to providing additional updates as we progress our work.
Mark: That concludes our prepared comments for today's call. Operator, you may now open the line for questions.
Marc Grasso: For 2025, we estimate our collaboration revenue to be between $5 and $15 million. Our anticipated total research and development expenses are estimated to be between $175 and $185 million. In total, general and administrative expenses are estimated to be between $55 and $65 million. We remain focused on advancing our broad and diverse portfolio as well as our electrobrain carrier technology to treat neurodegenerative We look forward to providing additional updates as we progress our work.
Speaker Change: Thank you as a reminder to ask a question. Please press star one on your telephone and wait for your name to be announced to withdraw your question. Please press star one again.
Speaker Change: And our first question will come from Pete Stavropoulos with Cantor Fitzgerald. Your line is now open.
Pete Stavropoulos: Hi, good afternoon, and congratulations on all the progress.
Pete Stavropoulos: One question for me is when you are thinking about the Infront study.
Marc Grasso: That concludes our prepared comments for today's call.
Operator: Operator, you may now open the line for questions. Thank you. As a reminder to ask a question please press star 11 on your telephone and wait for your name to be announced. To withdraw your question please press star 11 again.
Pete Stavropoulos: Earlier in the course of the neuro degenerative disease should result in greater clinical benefit and you see a larger separation between active arm and placebo.
Pete Stavropoulos: With that in mind for.
Pete Stavropoulos: For the baseline characteristics in front I believe 22% of the patients have a C. D. R. <unk> D <unk>.
Pete Stavropoulos: And the first question will come from Pete Stavropoulos with Cantor Fitzgerald. Your line is now open. Hi, good afternoon and congratulations on all the progress. One question for me is, you know, when you're thinking about the InFront study, you know, treating earlier in the course of a neurodegenerative disease, you know, 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 22% of the patients have a CDR FTLD, a global score of 0.5, 48% have a score of 1, 31% have a score of 2.
Pete Stavropoulos: Mobile score, 548% have a score of 131 have a score of two what gives you confidence that you enroll the correct proportion of patients for each score.
Pete Stavropoulos: Allow you to see a clear separation between <unk> and placebo and was there a cap for any of these patient populations.
Gary Romano: Yeah, Hi payments Gary Thanks for the question good question.
So we set out to enroll as you said this distribution of <unk> five to two.
Gary Romano: On the global score and this was intense.
Gary Romano: Intentional to try to target the early symptomatic population of FCB Grantland.
Gary Romano: And so.
Gary Romano: You know, what gives you confidence that you enrolled the correct proportion of patients for each score that will allow you to see a clear separation between latizendamide and placebo, and was there a cap for any of these patient populations? Yeah, hi, Kate, it's Gary. Thanks for the question. Good question. So, you know, we set out to enroll, as you said, this distribution of 0.5 to 2 on the global score. And this was intentional to try to target the early symptomatic population of FTD granulins. And so, you know, as you say, it's always a bit of a balance between trying to treat earlier where we think You know, we can imagine that there might be more room for greater efficacy, but also including patients that are that are a little bit further along and may may be progressing somewhat faster.
Gary Romano: As you say, if theres always a bit of a balance between trying to treat earlier, where we think.
Gary Romano: But we can imagine that there might be more room for <unk> four four for greater efficacy, but but also.
Gary Romano: Including patients that are that are a little bit further along and they may be.
Gary Romano: Be progressing somewhat faster. So this is.
Gary Romano: This is what we set out to do and and we're very happy that we were able to bring in that debt very population.
Gary Romano: We did cap.
Speaker Change: The CVR twos.
Gary Romano: And we reached that cap and stopped enrollment.
Gary Romano: Earlier.
Gary Romano: Two thirds or so through the trial and that was intentional because we didn't want to have too. Many patients are participants that were.
Gary Romano: Hadn't had more.
Gary Romano: It had been more further progressed and therefore, it might might not be as responsive to treatment theoretically and the other thing I just want to point out is even though that our primary analysis is focused on.
Gary Romano: So this is a you know this is what we set out to do and and we're very happy that we were able to bring in that that very population.
Gary Romano: Symptomatic subjects that we just discussed we also collected a small cohort of patients who are participants that were.
Gary Romano: We did cap the the CDR 2s at and we reached that cap it stopped enrollment earlier and you know about two-thirds or so through the trial and that was intentional because we didn't want to have too many patients or participants that were You know, had had more had been more further progressed and therefore might, might not be as responsive to treatment theoretically. The other thing I just want to point out is, even though the primary analysis is focused on the. Synthematic subjects that we just discussed.
Gary Romano: <unk>.
Gary Romano: Okay.
Gary Romano: Sure.
Gary Romano: I'm sorry.
Gary Romano: Mutation carriers, and but had a certain.
Gary Romano: A certain threshold of NFL neuro filament light.
Gary Romano: And we although we're not including those in the primary analysis.
Gary Romano: We will be looking at those patients with sensitivity analyses.
Gary Romano: In our analysis plan and that's the reason.
Gary Romano: Planning to do and and I think it's not a far stretch to think that if we can find the efficacy of the symptomatic subjects.
Unknown Speaker: We also collected a small cohort of patients who were participants that were last reflection Danielle full-time, And we will see you, in the next week. And we will see you in the next week.
Gary Romano: That there could be a potential.
Gary Romano: We also see a sensitivity analysis some benefit in the.
Gary Romano: Pre symptomatic.
Gary Romano: And patients are subjects that it wouldn't be a far stretch to think that we might you might be able to get some type of.
Gary Romano: Preliminary approval is pending.
Gary Romano: Pending some post marketing.
Gary Romano: Data.
Gary Romano: Why wait if it works in symptomatic subjects, why why should why should patients wait until their impaired to start treatment.
Unknown Speaker: Thank you! for , and Michael R. . Why wait? If it works in symptomatic subjects, why should patients wait until they're impaired? So follow up on that. Yeah, actually. Yeah. So when you do look at the the NFL levels of those 16 patients, that Thank you all so much. Yeah, good question again. So at the time that the study started and some years ago now, as you know, based on available data, the estimate was that those patients with the NFL threshold that we used in the study would progress within within two In fact, based on, you know, additional data that is quite a bit of additional data that's come out since then and analyses by the GenP and ROTD 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.
Gary Romano: So thanks for the question please.
Gary Romano: Yes.
Gary Romano: Yes, so when you do look at the NFL levels of those 16 patients that you.
Gary Romano: Enrolled pre symptomatic.
Gary Romano: And then you look at those as Gen. Five data are they is there an expectation that there is absolutely going to be progression within those 96 weeks.
Gary Romano: Yes, good question again.
Gary Romano: So at the time that the study started some years ago to now as you know.
Gary Romano: Based on available data the estimate was that those patients with the NFL threshold that we used in the study with progressed within it within two years impact based on additional data that is quite a bit of additional data that's come out since then analysis by the <unk> group.
Gary Romano: It has been published it now looks like the threshold, we use might have.
Gary Romano: We would be more along somewhere between two and four years to progressive symptomatic.
Gary Romano: So.
Gary Romano: If that was one of the reasons that we opted to focus our primary analysis on symptomatic subjects.
Gary Romano: But.
Gary Romano: Still we still expect some of these patients to have progressed.
Gary Romano: During during the study don't forget we are studying 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.
Gary Romano: Okay, Alright, thank you very much for taking our questions.
Speaker Change: Thanks Pete.
Speaker Change: And the next question will come from Alec Stranahan with Bank of America. Your line is open.
Unknown Speaker: So Unknown Speaker If that was one of the reasons that we opted to focus our primary analysis on symptomatic subjects. But, you know, it's still, we still expect some of these patients to have progressed and, you know, During the study, 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.
Alec Stranahan: Hey, guys. Thanks, Thanks for taking my questions just two from us.
Speaker Change: First on <unk> hundred one.
Alec Stranahan: Do you think.
Alec Stranahan: The shirt program program, you've been targeting there does there anything to read through from from in front of three years or is this maybe hard.
Alec Stranahan: Given the different.
Alec Stranahan: Indications and then.
Alec Stranahan: Second question I appreciate the new color on the ABC candidate nomination and maybe just walk us through the preclinical optimization that's going on.
Pete Stavropoulos: All right, thank you very much for taking our questions. Thanks Pete.
Alex Stranahan: And the next question will come from Alex Stranahan with Bank of America. Your line is open. Hey, guys. Thanks. Thanks for taking our questions. Just two from us.
Alec Stranahan: For these assets from here and sort of your thought process around bringing additional assets forward would be great. Thank you.
Alec Stranahan: Yes. So maybe this is Gary I'll start with answering your first question on <unk> hundred one and hand, it off to Sara.
Gary Romano: First, on AL-101, Do you think, you know, given the shared program, pro-granulin targeting, there's, there's anything to read through from, from in front three, or, or is this maybe hard given the different indications?
Alec Stranahan: Yeah.
Alec Stranahan: I don't we don't think that there's a read through from the Trump Trump China trials in this trial, just because the mechanisms are very different and.
Alec Stranahan: In this case, we are elevating.
Sara Kenkare: And then second question, appreciate the new color on the ABC candidate nominations, and maybe just walk us through the preclinical optimization that's going on for these assets from here and sort of your thought process around bringing additional assets forward would be great. Thank you.
Alec Stranahan: Elevating granular and which we believe is going to have effects, probably unlicensed zones.
Alec Stranahan: And whereas the <unk> was really a very specific approach to stimulate <unk> signaling that would increase microbial functions in a different way. So I don't think there's much of a 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 in the clinical outcome measures.
Gary Romano: Yeah, so maybe this is Gary, I'll start with answering your first question about L101 and hand it off to Sara. You know, I don't, we don't think that there's a read through from the TREM-2 trial to this trial, just because the mechanisms are so very different. And, you know, in this case, we're elevating granulin, which we believe is going to have effects probably on the lysosomes. And whereas the TREM-2 was really a very specific approach to stimulate TREM-2 signaling that would increase microbial functions in a different way. So I don't think there's much to read through there.
Alec Stranahan: We used to.
Alec Stranahan: We're trying to study performed very well, they're showing us a very definitive way and then we have a negative study Budd.
Alec Stranahan: So we are I am even more optimistic.
Alec Stranahan: That the Biomarkers will service very well again in this study in addition to the clinical outcomes and that we.
Alec Stranahan: We will get it will get a clear answer.
Alec Stranahan: And Alex if I heard your question right you were asking about 101, specifically and whether <unk> III would be.
Gary Romano: What I would say is that, in a positive way, is that we feel pretty confident now that the biomarkers that we used in the clinical outcome measures that we used in the TREM-2 study performed very well there, showing us, you know, in a very definitive way that we have a negative study. But, you know, 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. Alec, if I heard your question right, you were asking about 101 specifically and whether 1-3 would be tied to the outcome of Am I correcting that, Alec?
Tied to the ARPA of 101, Oh goodness that sorry, yes.
Alec Stranahan: And that out.
Alec Stranahan: Yes.
Alec Stranahan: It is.
Alec Stranahan: Thats helpful. My mistake, I thought I heard I thought I heard a $2 two okay I'm, sorry, yes, I mean I think.
Speaker Change: We are looking at those look I think again there is they are different in the mechanism. One is in the case of.
Speaker Change: The <unk> III study, that's the phase III study in FTE granular and these are patients that have a lifelong deficiency or have low insufficiency of granular <unk> and.
Speaker Change: Propositions, Jeff by normalizing that in an early stage of the disease, we can slow or stop the disease progression in Alzheimer's disease is different densities are.
Gary Romano: Yeah, but that, I mean, both is helpful. My mistake, yeah, I thought I heard 2.2. Okay, I'm sorry. Yeah, I mean, I think... We are looking at those. I think, again, they're different in the mechanism. One is, in the case of the 1-3 study, that's the phase 3 study in FDD granulin, these are patients that have a lifelong deficiency or haploinsufficiency of progranulin. And, you know, our hypothesis is that by normalizing that in an early stage of the disease, we can slow or stop the disease progression. In Alzheimer's disease, it's different. These are more...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.
Speaker Change: More.
Speaker Change: With the genetic show is there is that.
Speaker Change: Less severe.
Speaker Change: Patients that cause partial loss of function.
Speaker Change: Appeared to increase the risk of Alzheimer's disease, and so replacing it in that in that event could.
Speaker Change: Could be protective against Alzheimer's and there's also a fair amount of animal data, suggesting that increasing for granular levels can be protective against Alzheimer's patches geology. So so they are a little bit more wings certainly than the <unk>, but in the sense that it's all about for granular, but we can imagine scenarios, where one might be positive.
Speaker Change: The other.
Speaker Change: If one were negative the other could still be positive.
Speaker Change: I think your question was around our ABC preclinical programs. So maybe I'll just start and if you need more clarity can add further.
Gary Romano: 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 progranulin levels can be protective against Alzheimer's pathophysiology. So they're a little bit more linked, certainly, than the TRM-2, but in the sense that it's all about progranulin. But we could imagine scenarios where one might be positive. If one were negative, the other... Great.
Speaker Change: But as.
Speaker Change: As we said in our press release that actively progressing.
Speaker Change: Several preclinical programs certainly.
Speaker Change: So those are ADP or three seven ABC, which is our anti amyloid beta antibody.
Speaker Change: The ADC program and the other is ADP 050, which is our <unk> replacement therapy for Parkinson's disease now these programs.
Speaker Change: Our advance and our goal is to.
Sara Kenkare: I think your question was around our ABC preclinical program.
Speaker Change: To get to an IND submission and to be in the clinic in 2026.
Sara Kenkare: So maybe I'll just start. And if you need more clarity, you can ask further. But we you know, as we said in a press release, we are actively progressing several preclinical programs. Certainly the most advanced of those are ADP 037 ABC, which is our anti amyloid beta antibody ABC program. And the other is ADP 050, which is a GK replacement therapy for Parkinson's disease. These programs are more advanced. And, you know, our goal is to to get to an IND submission and to be in the clinic in 2026.
Speaker Change: Besides that we're also applying our ADC technology too.
Speaker Change: To target Tau and making two different approaches day, one is an antibody approach the other is.
Speaker Change: Tao.
Speaker Change: These are not as far along as the two programs I mentioned.
Speaker Change: We also have a <unk> modulator that is designed to block hour pathology and promotes synaptic function in Alzheimer's disease.
Speaker Change: And thirdly at this moment I mean, if you have any other questions around this I'm happy to answer them.
Speaker Change: That's very helpful. Thank you for the color.
Sara Kenkare: 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. These are not as further along as the two programs I mentioned. We also have a really modulator that is designed to block tau pathology and promote synaptic functions in Alzheimer's disease. And and certainly, you know, at this moment, I mean, if you have any other questions around this, I'm happy to answer.
Speaker Change: Okay.
Speaker Change: And our next question will come from Paul Matteis with Stifel. Your line is now open.
Speaker Change: Hi, This is Emily on for Paul just to kind of ask a little bit more about your ADC platform could you maybe highlight some of the key differences with your blood brain barrier platform with others such as like can all hear Roche effort and then also just a bit more specifically on ADP easier 370.
Speaker Change: Could you maybe talk a little bit.
Speaker Change: More about the rationale for selecting those as your first two targets. Thank you.
Unknown Speaker: That's very helpful. Thank you for the call.
Speaker Change: Yeah, I can take that maybe arent and you can add so I think firstly can get to your question about our electorate ADC technology.
Emily: And our next question will come from Paul Mattheis with CFEL. Your line is now open. Hi, this is Emily on for Paul.
Speaker Change: It stands out in several ways, Firstly say that our toolbox approach is versatile and tunable and as you know with ABC as youre trying to maximize efficacy while minimizing the potential.
Sara Kenkare: 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 gnarly or Roche efforts? And then also just a bit more specifically on ADP 037 and 050? Could you maybe talk a little bit more about the rationale of like selecting those as your first two targets? Thank you. Yeah, I can I can take that. Maybe Arnon, you can add.
Speaker Change: Safety Tolerability and I think what our technology provides.
Speaker Change: <unk> provides for that very well because of that for the first utility it's not as rigid we can fine tune book.
Speaker Change: 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 they tunable.
Sara Kenkare: 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. 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 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.
Speaker Change: And very adaptable platform that we can apply depending on whether it's an antibody protein letting you need NFC or you don't need NFC et cetera, now coming to our two different programs Adp's iOS, seven ADC, which is our MLR.
Speaker Change: <unk> data technology.
Speaker Change: We believe.
Speaker Change: Firstly it targets a validated epitope such as the <unk> III, a beta epitope, which is.
Sara Kenkare: 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. Now, coming to our two different programs, ADP037ABC, which is our AAB amyloid beta technology, I, you know, we believe that firstly, it targets a validated epitope, which is the pyroglut3 A-beta epitope, which is, which, you know, 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 also sort of configuring the affinity to TFR, 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.
Speaker Change: Rich.
Speaker Change: With our brain brain Penetrant ABC, we also have a fully active at sea, which allow which is essential for the cyber cytosis of amyloid beta plaque.
Speaker Change: And we also sort of configuring the affinity to TFR.
Speaker Change: We've been able to fine tune it to allow us to get sort of the.
Speaker Change: The optimal half life minimal safety as well as maximal pain penetration not certainly this is all preclinical, but we believe that the combination of all of this allows ABC.
Speaker Change: <unk> ADP 037, ABC to have the potential to be best in class molecule in the future.
Speaker Change: Now ADP 050.
Speaker Change: <unk>, which is our <unk> ADC program.
Speaker Change: In targeting Parkinson's disease again, we are developing that this is our natural gk's debate unstable and shortlist molecule, we've engineered a much more stable and active gk's enzyme Terminator Genesis, which also has a minimal potential to be.
Sara Kenkare: Now, certainly this is all preclinical, but we believe that the combination of all of this allows ABC, ADP037ABC, to have the potential to be a best-in-class molecule in the future.
Speaker Change: Immunogenic.
Speaker Change: And ADP all slides veto.
Speaker Change: <unk>.
Speaker Change: Paired with our ADC technology.
Sara Kenkare: Now, ADP050-ABC, which is our GK's ABC program in targeting Parkinson's disease, again, we are developing that this is our natural GK's is a very unstable and short-lived molecule. We've engineered a much more stable and active GK's enzyme through mutagenesis, which also has 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. Great, thank you guys so much.
Speaker Change: Really could enable brain penetration and the potential for you.
Speaker Change: So for treatment of Parkinson's disease.
Speaker Change: Great. Thank you guys so much.
Speaker Change: The next question will come from Tom Shrader with <unk>. Your line is open.
Speaker Change: Good afternoon. Thanks for taking the question more on the shuttle I'm afraid.
Speaker Change: Can you talk a little bit about your decision to use SA RNA versus ASO I think almost everyone else is on the ASO side and specifically are there. Good preclinical models for some of the problems of Dsos can run into like inflammation and protein buildup. When will you know if thats a differentiated approach and maybe.
Speaker Change: Any thoughts you have about why you took this approach.
Tom Shrader: The next question will come from Tom Shrader with BTIG. Your line is open. Good afternoon. Thanks for taking the question. More on the shuttle, I'm afraid.
Speaker Change: It seems as if the field is moving towards.
Speaker Change: So.
Speaker Change: It seems as if.
Speaker Change: That's fair.
Speaker Change: More a better on target activity for the fuel side effect better stability.
Unknown Speaker: Can you talk a little bit about your decision to use siRNA versus ASOs? I think almost everyone else is on the ASO side. And specifically, are there good preclinical models for some of the problems that ASOs can run into, like inflammation and protein buildup? When will you know if that's a differentiated approach? And maybe any thoughts you have about why you took this approach? It seems as if the field is moving to siRNA from ASO. It seems as if siRNAs have more, a better on-target activity, sort of fewer side effects, better stability. But yeah, we are testing it now.
Speaker Change: But yes, we are testing it now.
Knowing the next six months or so.
Speaker Change: How good it is.
Speaker Change: Look at the literature, if you compare the side by side, the efficacy of or let's.
Speaker Change: For example against.
Speaker Change: But robin vacations.
Speaker Change: More important to me.
Speaker Change: Sort of blocking that target so it seems as if now.
Speaker Change: Efficacy advantage as well as safety advantages. So but you are right. This is just an evolving field.
Speaker Change: For each of the total growth technologies.
Unknown Speaker: And yeah, 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 ASO versus siRNA, for example, against tau, there are indications that siRNA is more potent in sort of blocking the target. So it seems as if there are some efficacy advantages as well as safety advantages. But you're right, this is just an evolving field and we'll see which of the two nucleic acid technologies is better.
Speaker Change: A quick follow up is is this is this do you see this isn't.
Speaker Change: A good place for M&A, and some sort of another big deal or the most companies have the technology. They won is that something we should be looking for as you out licensing some piece of your technology for some non dilutive funding.
Speaker Change: Okay.
Speaker Change: Sure.
Speaker Change: But I've been bearish I believe still.
Speaker Change: Still a technology that multiple companies are seeking.
Speaker Change: Eh.
Speaker Change: The activity.
Speaker Change: So the few companies, even mature broken barrier technologies and most of the companies with good technology, though.
Unknown Speaker: A quick follow up. Is this is this do you see this as a good place for M&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? Is you out licensing some piece of your technology for some non diluted funding? means that the sort of blood and bare shatter is still a technology that more multiple companies are seeking means that they'll have to be So the few companies with mature black and white technologies and most of the companies with good technologies are sort of either engaged already or are going to be quite expensive.
Speaker Change: Either engaged already or are going to be quite expensive. So I think that.
Speaker Change: Conceptually there is a lot of it through we feel a lot of inbound interest and there is a lot of interest in our technology and again.
Speaker Change: Paul.
Speaker Change: Conceptually could be <unk>.
Speaker Change: For antibody therapeutics.
Speaker Change: Therapy nucleic acid therapy, it could improve.
Speaker Change: Sort of the convenience of delivery from interfering with the subcutaneous.
Speaker Change: In the case of <unk>.
Speaker Change: It couldn't.
Speaker Change: Reduce or possibly even eliminate avia like adverse effect. So I think there is a lot of interest in the technology and I think that.
Unknown Speaker: So I think that conceptually, there is a lot of, we see a lot of interest and there is a lot of interest in our technology. And again, because it conceptually could be utilized for antibody therapeutics, enzyme replacement therapy, nucleic acid therapy, it could improve sort of the convenience of delivery from intravenous to subcutaneous. In the case of Alzheimer's disease, it can sort of reduce or possibly even eliminate area-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.
Speaker Change: Even though the.
Speaker Change: The technology is conceptually.
Speaker Change: To really optimize.
Speaker Change: But really thread this needle between efficacy and safety is not so easy and I think that actually only two or three companies.
Speaker Change: The module technology.
Speaker Change: Phil.
Speaker Change: A lot of demand for the commodity.
Speaker Change: Great. Thank you for the color.
Speaker Change: Thanks, Tom.
Speaker Change: The next question comes from Iran, Werber with TD Cowen Your line is open.
Iran Werber: Great. Thanks for taking my question I have a question maybe on infant three as you're looking at the primary endpoint in symptomatic patients can you give us a sense just remind us how it is powered.
Speaker Change: And.
Unknown Speaker: And I think there are actually only two or three companies that have the mature technology. So there is still, I think, a lot of demand for the technology.
Speaker Change: 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 are you going to continue to follow up at that point onwards. Thank you.
Ron: Yeah, Thanks, Ron and good questions.
Unknown Speaker: Great. Thank you for the call. Thanks, Tom.
Ron: So the study is powered for approximately 90%.
Yaron Werber: The next question comes from Yaron Werber with TD Co. and your line is open. Great. Thanks for taking my question. I had a question maybe on infant three. As you're looking at the primary endpoint in symptomatic patients, can you give us a sense, just remind us how it's powered? And just remind us also, the data that we're going to see by year end, do you think that's going to be the fully mature data? Or are you going to continue to follow up at that point onwards? Thank you. Yeah, thanks, Ron. Good questions. So the study is powered for approximately 90%.
Ron: Roughly 90% power to detect a 40% slowing of disease progression and if our study design assumptions hold.
Ron: With regard to.
Ron: Personality and dropouts from which we expect.
Ron: If we observe a 25% slowing of disease progression at the end of the study and we expect that that will be a positive.
A positive feedback so so I hope that answers your question about the about the power.
Ron: The second part of your question.
Ron: Whether it's going to be all the data together, yes, Im sorry, Greg.
Gary Romano: We have about approximately 90% power to detect a 40% slowing of disease progression. And if our study design assumptions hold in, you know, with regard to I hope that answers your question about the power.
Ron: Yeah. So.
Ron: This will include it this will be all of the data it'll be two years of data on all participants' 96 week.
Ron: The data on all participants.
Ron: Data from a long term extension that we will also be looking at which is inflation as I mentioned earlier, we've had patients now.
Ron: In the long term extension for as long as four years up to four years.
Ron: And also supporting Biomarkers as well.
Gary Romano: second part of your question What's whether it's going to be all the data together? Yeah, I'm sorry. Right. Yeah, so This will include, this will be all of the data. It'll be two years of data on all participants, 96 weeks of data on plus data from a long-term extension that we'll also. As I mentioned earlier, we've had patients now in the long-term extension for as long as four years.
Ron: Yes.
Ron: In addition to the primary endpoint I'll remind you that we had a meeting.
Ron: Meeting with FDA.
Ron: Middle of last year under our breakthrough designation status.
Ron: We discussed a number of Biomarkers and.
Ron: It was very encouraging.
Ron:
Ron: We agreed to that.
Ron: We came to agreement that we could use in.
Ron: In addition to the consequent to the product line points. We can also went into the <unk>.
Ron: The changes in or treatment related changes in programming levels with the CSF and plasma which would be considered as confirmatory evidence.
Gary Romano: and also supporting Biomark. Yeah, so in addition to the primary endpoint, you know, I'll remind you that we had a meeting with FDA in the middle of last year, under our breakthrough designation status, where we discussed a number of biomarkers, and it was very encouraging. They agreed that...we came to agreement that we could use, in addition to the primary clinical endpoints, we can also lean into the changes, or treatment-related changes in programming levels, both in CSF and plasma, which would be considered as confirmatory evidence, and we also discussed a number of fluid and imaging biomarkers that we felt were important to discuss.
Ron: And we also discussed a number of fluid and imaging Biomarkers that we felt we made the case.
Ron: That should be predictive of clinical benefit.
Ron: And they also agreed that those.
Ron: Biomarkers would be looked at as essentially supportive of clinical data. So I think.
Ron: Kind of wrapping it all up.
Ron: We are feeling optimistic that FDA is going to look at the totality of the data.
Ron: And what are the clinical outcomes and Biomarkers and that in this rare very rare disease. There's just no other treatments.
Ron: It gives us a good chance we are planning for a full approval.
Ron: First off the primary endpoint.
Ron: The ctr, but.
Gary Romano: 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, you know, kind of wrapping that all up, you know, we're feeling optimistic that FDA is going to look at the totality of the data and both clinical outcomes and biomarkers and that in this, you know, rare, very rare disease where there's no other treatments.
Ron: But if for some reason the unexpected ways. The primary endpoint disappoints I think we're going to have a lot of other potentially supported data that could be.
Ron: It gives us a backup plan.
Speaker Change: Thanks, Rob.
Speaker Change: And the next question will come from Sara SRAM with William Blair. Your line is open.
Sara SRAM: Thanks, guys. Thanks for taking my question, so going back a little bit to the preclinical programs can you just remind us specifically how of that pair of Laramie.
Yaron Werber: We are planning for a full approval, you know, based first off the primary endpoint, the CDR, but I'm But, you know, if for some reason the unexpectedly the the primary endpoint disappoints, I think, you know, we're going to have a lot of other potentially supported data that could be, you know, give us a backup plan. Thanks, you're.
Sara SRAM: <unk> beta epitope that you're targeting with your three seven differs from both the approved a beta antibodies as well as some of the other ones in development like <unk>, which does also use the brainchild technology and kind of how those different epitopes might lead to differentiation and could you also just remind us if that seven eases, the TFR or a Cte 98 mediator.
Sara SRAM: Grain shuttles system.
Sarah Schramm: And the next question will come from Sarah Schramm with William Blair. Your line is open. Thanks, guys. Thanks for taking the question.
So firstly I mean, if we let's go to the ton Panama molecules target. The in terminal region of amyloid beta versus our program ADP or three seven targets the Pye-dog Lou.
Sara Kenkare: So going back a little bit to the preclinical program, can you just remind us, you know, specifically how that pyroglutamate A-beta epitope that you're targeting with 037 differs from both, you know, the approved A-beta antibodies, as well as some of the other ones in development, like Tartunumab, which does also use a brain shuttle technology, and kind of how those differing epitopes might lead to differentiation. And could you also just remind us if 037 uses a TFR or a CD98 mediated brain shuttle system? Thanks. Yeah so firstly I mean if you let's go to the Trontanamab molecule targets the N-terminal region of amyloid beta versus our program ADP037 targets the pyroglue 3A beta epitope which actually is similar to the epitope in and I think the second part of your question Could you repeat the second part of your question, sorry, Sara?
Sara SRAM: A beta epitope, which actually is similar to the epitope in done on a map and then turn it to <unk>.
Sara SRAM: And I think the second part of your question.
Sara SRAM: Could you repeat the second part of your question sorry, Yeah, Yeah sure. So like how how might the different epitopes lead to differentiation in terms of targeting potentially different plant species.
Sara SRAM: Yeah, I mean, I think the way we see it is that the.
Sara SRAM: Because we are targeting the pyro blue tree EBIT to EBITDA, which is a validated epitope.
Sara SRAM: Certainly that that.
Sara SRAM: Has been demonstrated as a naked antibody could be effective and so that's wonderful as you know.
Sara SRAM: <unk> molecule is based.
Sara SRAM: Is it is a shuttle enabled.
Sara SRAM: Molecule.
Sara Kenkare: Yeah, sure. So, like, how might the different epitopes lead to differentiation in terms of targeting potentially different plaque species? Yeah, I mean, I think the way we see it is that you the because we're targeting the pyroglutarate a beta epitope, which is a validated epitope, you know, certainly that that has been demonstrated as a naked antibody to be effective. And so that's that's wonderful. As you know, the trontenamide molecule is based is a is a shuttle enabled molecule. The naked molecule, gantanamide, was not effective in the clinic. And so I think that goes really well to using a pyroglutarate a beta epitope in our ABC construct.
Sara SRAM: The naked molecule can connect them up was not effective in the clinic and I said I think that bodes really well to using our <unk> III <unk> epitope in our ADC construct.
Sara SRAM: And then in addition, as I said, we have a fully active at sea and more importantly, we fine tuned our affinity for TFR I think one of your questions was using <unk> and beyond for this.
Sara SRAM: This molecule.
Sara SRAM: We have configured the affinity to TFR and to optimize it to have them.
Sara SRAM: Minimal safety.
Sara SRAM: RBC reductions.
And optimum half life and then penetration.
Sara SRAM: Got it very helpful. Thank you.
Sara SRAM: Thank you Sir.
Speaker Change: A reminder to ask a question. Please press star one on your telephone and the next question comes from Sam Lee.
Sara Kenkare: 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, you know, sort of minimal safety, RBC reduction, and optimal half-life and brain benefit. Got it. Very helpful. Thank you. As a reminder, to ask a question, please press star 1 1 on your telephone.
Moderator: MS. Xu your line is now.
Speaker Change: Yes.
Speaker Change: So Greg savanna, thanks for taking our questions a couple on our end.
Speaker Change: In fund III can you please remind us how you've enrich for patients more generally optimize the trial design in order to give yourself the best chance of success for us to show efficacy.
Speaker Change: And also an STD knowing that there are several programs in clinical development can you compare and contrast, your approach versus the competitive programs and why do you think a lot other than a mab may offer an optimal therapeutic option when compared to the other programs. Thank you so much.
Unknown Speaker: And the next question comes from Sam Lee with Mizuho. Your line is now open. Hi, this is Sam.
Speaker Change: Yeah. Thanks, I'm going to have to ask you to repeat the first part of your question because there's a lot of background noise coming over with us sorry about that.
Greg Suvannavejh: Hi, this is Greg Suvannavejh. Thanks for taking our questions. A couple on our end.
Speaker Change: Sure.
Speaker Change: For the rest of the question for <unk> can you just remind us how you've enriched for patients.
Gary Romano: For InFront3, can you please remind us how you've enriched for patients and more generally optimized the trial design in order to give yourself the best chance of success?
Speaker Change: I would really like optimize the trial design to get the best chance of success to show efficacy.
Speaker Change: And then the second question with regard to just the competitive landscape for FTE like knowing that there are several programs in clinical development can you just remind us of like the differentiating factors of.
Gary Romano: 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 a lot of them may offer an optimal therapeutic option when compared to the other programs? Thank you. Yeah, thanks. I'm gonna 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. Sure. Just repeating for the first question, for In Front 3, can you just remind us how you've enriched for patients and more generally, like, optimized the trial design to get the best chance of success to show efficacy?
Compare contrast, the approach and lie.
Speaker Change: Perhaps it might offer optimal therapeutic option.
Yes, thanks, so so.
Luis: Luis Thank you for that so.
Speaker Change: This was that this was this.
Luis: Anthony Grand home patients, while they're out there.
Speaker Change: Because of under diagnosis in general and also.
Speaker Change: When we started this there wasn't a lot of genetic testing and they're difficult to find.
Gary Romano: And then the second question with regard to just the competitive landscape for FTD, like, knowing that there's several programs and clinical development, can you just remind us of, like, the differentiating factors of LATA, ZITIMAB, compare and contrast the approach, and why perhaps it might offer an optimal therapeutic option? Yeah, thanks. So, so let me thank you, thank you for that. So, so, you know, this was a, this was a, these FDD granulone patients, while they're out there, because of under diagnosis, in general, and also, you know, when we started this, there wasn't a lot of genetic testing, they're difficult to find, I mean, in terms of enriching, you know, we just, we really just looked with where the patients were, you know, there were, there are pockets of patients in different countries, in Italy, in Portugal, et cetera, and other, other, you know, where there are founder effects.
Speaker Change: In terms of enriching, we just we'd really just looked.
We are the patients where there were.
Speaker Change: There are pockets of patients in different countries in Italy, and Portugal et cetera, and other other.
Speaker Change: Whenever its founder effects. We went there we built the relationships with the sites and we were able to enroll as I've said eventually over 100 <unk> hundred three symptomatic subjects.
Speaker Change: The trial design, we really never.
Speaker Change: The trial design is not really the trial execution has not changed in this trial started.
Speaker Change: The plan was somewhat opportunistically too.
Speaker Change: NOI, both symptomatic and the pre symptomatic and the same at the same time, we found that as I mentioned earlier that with more data being collected in the.
Speaker Change: In the observational studies generally in all of TD and we learned a few things over that's over the time that we were enrolling studying one is that.
Gary Romano: We went there, we built the relationships with the sites, and we were able to enroll, as I said, eventually over 100, 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 sought optimistically to analyze both the symptomatic and the pre-symptomatic in the same, at the same time. We found that, as I mentioned earlier, that with more data being collected in the, in the observational studies, GENPHY and all FDD, we learned a few things over the, over the time that we were enrolling in the study.
Speaker Change: There was.
Speaker Change: The greater variability of progression in the pre symptomatic because they really they don't progressed pretty quickly.
Speaker Change: And for that reason.
Speaker Change: One of the reasons, we decided to focus the primary analysis on the symptomatic subjects and it can be described.
Speaker Change: And that was reviewed with FDA and EMA and they were actually both very pleased that we were doing that.
Speaker Change: And as I mentioned earlier, we will also look still look at those.
Speaker Change: Pre symptomatic and a sensitivity analysis.
Speaker Change: Terms of how does our approach differ differentiate from others.
Gary Romano: One is that, There was a greater variability of progression in the pre-symptomatic because they really , and lot of V d more . And as I mentioned earlier, we'll also still look at those pre-symptomatics and the sensitivity now. In terms of how does our approach differentiate from others, you know, What we do is bring, you know, our mechanism by blocking sirtillin in the receptor increases the progranulone levels back to normal range. And you know, we've shown in our phase two study that this, if you do that, that you see normalization of a number of biomarkers.
Speaker Change: Yeah.
Speaker Change: What we do is is bringing for grandma or mechanism by blocking <unk> receptor increase.
Speaker Change: Increases.
Speaker Change: <unk>.
Speaker Change: For granular levels back to normal range.
Speaker Change: And we've we've shown in our phase II study.
Speaker Change: That this if you do that that you see normalization of the number of Biomarkers, where we start.
Speaker Change: Gross inflammatory biomarkers.
Speaker Change: Biomarkers of lysosomal function, we saw a normalization of G fast we saw.
A slowing in NFL accumulation.
Speaker Change: And we also saw changes on <unk>.
Speaker Change: Imaging on volumetric MRI.
Speaker Change: So so and beyond that we did a.
Speaker Change: A entity matched comparison of the <unk>.
Speaker Change: Subjects in our phase one study two.
Speaker Change: Baseline density matched patients from the Gen feed study and that showed a slowing of disease progression by up to 48%. So we think we for all those reasons. We believe that this is having an effect on.
Gary Romano: both inflammatory biomarkers, biomarkers of lysosomal function. We saw a normalization of PFAP. We saw a slowing of NFL accumulation. And we also saw changes on imaging on volumetric MRI. So, so and beyond that, we did a, a density matched comparison of the subjects in our in our phase one study to a baseline density matched patients from the GENPHY study, and that showed a slowing of disease progression by 48%. So we think we, for all those reasons, we believe that this is having an effect on the pathophysiology.
Speaker Change: Patrick on the pathophysiology.
Speaker Change: I can't in terms of the other approaches whether it's a gene therapy or delivery engine.
Speaker Change: Delivering the protein directly.
I think it's too soon to say I mean, it may be that.
Speaker Change: There's always the potential for granular is a very ubiquitous protein with many functions and.
Speaker Change: We get a little nervous when we think about increasing the granting levels well above normal.
Speaker Change: R R.
Speaker Change: <unk>.
Speaker Change: Normalizing for them. So I think we'll know with time, whether weather, whether more is better or whether some of these other approaches are more or less effective but were pretty far behind it.
Gary Romano: I can't, you know, 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 You know, there's always the potential. Progranulin is a very ubiquitous protein with many functions, and, you know, we get a little nervous when we think about increasing progranulin levels well above normal. But, you know, our approach normalizes them. So, I think we'll know with time, you know, whether more is better or whether some of these other approaches are more or less effective, but they're pretty far behind.
Speaker Change: Instead, we were months away from from a readout on our phase III study.
Speaker Change: We're quite optimistic.
Speaker Change: That's really helpful color. Thank you so much.
Mark: I show no further questions at this time I would now like to turn the call back over to Mark for closing remarks.
Mark: Thank you operator before we end the conference call I'd, just like to share that electric will be participating in a number of upcoming conferences, including TD Cowen 45th Annual Health Care Conference next week on March 4th in Boston will be there.
Unknown Speaker: We're months away from a readout on our Phase 3 study. That's really helpful, caller. Thank you so much. I show no further questions at this time.
Mark: <unk> 2025 Global Biopharma conference. The following week, we'll be there Marshall Lemon and Miami and we're also looking forward to Staples 2000, 22025 virtual CNS Forum on March 18th.
Marc Grasso: I would now like to turn the call back over to Marc for closing remarks. Thank you, operator. Before we end the conference call, I'd just like to share that Alector will be participating in a number of upcoming conferences, including T.D. Cowan's 45th Annual Healthcare Conference next week, March 4th in Boston, we'll be there. Larynx 2025 Global Biopharma Conference the following week, we'll be there March 11th in Miami.
Thank you again for your time and attention and we will now conclude today's call.
Speaker Change: Thank you. This does conclude today's conference call. Thank you for participating you may now disconnect.
Marc Grasso: And we're also looking forward to Stiefel's 2025 Virtual CNS Forum on March Thank you again for your time and attention, and we will now conclude today's call. Thank you. This does conclude today's conference call. Thank you for participating. You may now disconnect. Goodbye.