Q2 2024 Alector Inc Earnings Call

Operator: Good afternoon, ladies and gentlemen, and welcome to the Elector second quarter and midterm mid year 2024 earnings conference call. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 11 on your telephone. You will then hear an automated message advising that your hand is raised. To withdraw your question, please press star 118. As a reminder, this conference call is being recorded. I would now like to turn the call over to Katie Hogan, Senior Director of Corporate Communications and Investor Relations.

Operator: Good afternoon, ladies and gentlemen, and welcome to the Elector's second quarter and mid-term mid-year 2024 earnings conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star 1-1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 1-1 again. As a reminder, this conference call is being recorded.

Thank you.

Speaker Change: Good afternoon, ladies and gentlemen, and welcome to the Elector Second Quarter and Mid-Year 2024 Earnings Conference Call.

Speaker Change: At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star-one-one on your telephone.

Speaker Change: You will then hear an automated message advising your hand is raised.

Speaker Change: To withdraw your question, please press star 1 1 again.

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.

Speaker Change: As a reminder, this conference call is being recorded.

Speaker Change: I would now like to turn the call over to Katie Hogan, Senior Director of Corporate Communications and Investor Relations.

Katie Hogan: Thank you, operator, and hello everyone. Earlier this afternoon, we released our financial results for the second quarter 2024. The press release is available on our website at www.elector.com. And our 10-K was filed with the Securities and Exchange Commission this afternoon.

Katie Hogan: Thank you, operator. And hello, everyone.

Speaker Change: Please go ahead.

Katie Hogan: Thank you, Operator, and hello, everyone. Earlier this afternoon, we released our financial results for the second quarter, 2024.

Katie Hogan: Earlier this afternoon, we released our financial results for the second quarter of 2024. The press release is available on our website at www.elector.com. And our 10-Q is filed with the Securities and Exchange Commission this afternoon. 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.

Speaker Change: The press release is available on our website at www.elector.com. And our 10-Q is filed with the Securities and Exchange Commission this afternoon.

Katie Hogan: Joining me on the call today are Dr. Arnon Rosenthal, co-founder and CEO, Dr. Sara Kenkare Neetress, 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 know 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'd also encourage you to review our FCC filing for more information.

Speaker Change: Joining me on the call today are Dr. Arnon Rosenthal, co-founder and CEO , Dr. Sara Kenkare-Nietzsche, President and Head of Research and Development, Dr. Gary Romano, Chief Medical Officer, and Dr. Marc Grasso, Chief Financial Officer.

Katie Hogan: 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 in the webcast, which contains our forward-looking statement disclosure. And we also encourage you to review our FCC filings for more information. I would now like to turn the call over to Arnon Rosenthal, Chief Executive Officer. Arnon? Thank you, Katie.

Speaker Change: 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 in the webcast, which contains our forward-looking statement disclosure, and we also encourage you to review our SEC filings for more information.

Arnon Rosenthal: I would now like to turn the call over to Arnon Rosenthal, Chief Executive Officer. Arnon. Thank you, Katie. Good afternoon, everyone. We appreciate you joining our conference call today.

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

Arnon Rosenthal: Thank you, Katie. Good afternoon, everyone.

Arnon Rosenthal: We appreciate you joining our conference call today. I'll start by highlighting Alector's key initiatives during the first half of 2024. Then, I'll invite Gary to discuss our later stage clinical program. Next, Sara will share the progress we believe we have achieved with Alector's Brain Carrier, our proprietary versatile blood-brain barrier technology platform. Afterward, Marc will provide an update on our financial results and milestone outcomes. During the first half of 2024, we remain committed to advancing our maturing pipeline and are setting the stage for a transformative period ahead.

Arnon Rosenthal: Thank you, Katie. Good afternoon, everyone.

Arnon Rosenthal: I'll start by highlighting elect of key initiatives during the first half of 2024. Then, I'd invite Gary to discuss our later stage clinical program. Next, Sara will show that the progress we believe we have achieved with elective brain carrier, our proprietary versatile blood and various technology platforms. Afterwards, Marc will provide an update on our financial results and milestone outlook. During the first half of 2024, we remain committed to advancing our maturing pipeline and are setting the stage for a transformative period ahead. Specifically, we continue to prepare for the data readout from the L-002 Phase Two trial in VOG2 expected in Q4.

Arnon Rosenthal: We appreciate you joining our conference call today.

Arnon Rosenthal: I'll start by highlighting Alector's key initiatives during the first half of 2024.

Arnon Rosenthal: Then, I'll invite Gary to discuss our later stage clinical programs.

Arnon Rosenthal: Next, Sara will share the progress we believe we have achieved with Alector's Brain Carrier, our proprietary, versatile, blood-brain barrier technology platform.

Arnon Rosenthal: Afterward, Marc will provide an update on our financial results and milestone outlook.

Arnon Rosenthal: During the first half of 2024, we remain committed to advancing our maturing pipeline and are setting the stage for a transformative period ahead.

Arnon Rosenthal: Specifically, we continue to prepare for the data readout from the AL002 Phase 2 trial in VOG2, expected in Q4. L002, our novel TRM-2 agonist, aims to enhance TRM-2 signaling and activate the healthy and beneficial role that microglia play in the setting of neurodegenerative disease. This immunoneurology approach leverages multiple mechanisms of healthy microglia to protect the brain against Alzheimer's disease, potentially offering an efficacy advantage compared to current therapies that target individual misfolded proteins.

Marc: Specifically, we continue to prepare for the data readout from the AL002 Phase 2 trial in VOG2, expected in Q4.

Arnon Rosenthal: L-002, our novel Trump II agonist, aims to enhance Trump II signaling and activate the healthy and beneficial roles that my co-glia play in the setting of Northern Generative Diseases. This immunology approach leverages multiple mechanisms of healthy my co-glia to protect the brain against Alzheimer's disease, potentially offering an efficacy advantage compared to Clarence therapies.

Marc: L002, our novel TRM-2 agonist, aims to enhance TRM-2 signaling and activate the healthy and beneficial role that microglia play in the setting of neurodegenerative diseases.

Marc: This immuno-neurology approach leverages multiple mechanisms of healthy microglia to protect the brain against Alzheimer's disease.

Arnon Rosenthal: The target individual is for the proteins. L-002 is the most advanced Trump II activating candidate in clinical development worldwide, with potential as a monotherapy or as an add-on therapy with anti-amilia. Today, we will discuss the patient baseline characteristics reported for Invoke Two trials at the Alzheimer's Association International Conference in July. These characteristics confirm a representative study population that enables testing of the effect of AL-002 in early Alzheimer's disease. We will also delve into the multiple clinical trials imaging and biomarkers readouts for the Invoke Two trials. Our common closed design and statistical PMMRM analysis and our long-term extension study, all for which were designed to strengthen the trial analysis.

Marc: Potentially offering an efficacy advantage compared to current therapies that target individual misfolded proteins.

Arnon Rosenthal: AL002 is the most advanced TRUMP II activating candidate in clinical development worldwide, with potential as a monotherapy or as an add-on therapy with anti-amyloid. Today we will discuss the patient baseline characteristics reported for the Invoke 2 trial at the Alzheimer's Association International Conference in July. These characteristics confirm a representative study in a population that enables testing of the effect of AL002 in early Alzheimer's disease. We will also discuss the multiple clinical trial imaging and biomarker readouts for the INVOK2 trial. Our Common Clause Design and Statistical PMMRM Analysis, and our long-term extension study, all of which were designed to strengthen the trial analysis. Additionally, Gary will share our thoughts on what a successful data readout looks like.

Marc: AL002 is the most advanced TRAM2 activating candidate in clinical development worldwide.

Marc: with potential as a monotherapy or as an add-on therapy with anti-amyloids.

Marc: Today we will discuss

Marc: The patient baseline characteristics reported for INVOG-2 trial at the Alzheimer's Association International Conference in July .

Marc: These characteristics confirm a representative study in population that enables testing of the effect of AL002 in early Alzheimer's disease.

Marc: We will also delve into the multiple clinical trial imaging and biomarkers readouts for the INVOKE-II trial.

Speaker Change: Our Common Clause Design and Statistical BM-MRM Analysis

Speaker Change: and our long-term extension study.

Speaker Change: All of which were designed to strengthen the trial analysis.

Gary Romano: Additionally, Gary will share our thoughts on what the successful data without look like.

Gary: Additionally, Gary will share our thoughts on what a successful data readout looks like.

Arnon Rosenthal: In February 2024, the FDA granted Breakthrough Therapy designation to Ratozina Mob for the potential treatment of STB with GRM mutations. You may recall that Ratozina Mob is a monoclonal antibody that elevates the level of the immune regulatory protein programmable by blocking so thinning. The breakthrough designation that provided the opportunity for increasing interactions with the FDA on this program. And now we have additional clarity on how key biomarkers make the portal path to a potential regulatory submission. We will provide more details on this FDA feedback during today's call. Looking ahead, we believe that we haven't track for the pivotal phase three data readouts from in front three trials in late 2025, early 2026.

Arnon Rosenthal: In February 2024, the FDA granted breakthrough therapy designation to latozinamab for the potential treatment of STDs with zero amputation. You may recall that latozinamab is a monoclonal antibody that elevates the level of the immune regulatory protein progranulin by blocking sirtiline. The breakthrough designation provided the opportunity for increased interactions with the FDA on this program, and now we have additional clarity on how key biomarkers may support our path to a potential regulatory submission.

Gary: In February 2024, the FDA granted a breakthrough therapy designation to latozinumab for the potential treatment of FTD.

Gary: with GRM mutations.

Gary: You may recall that latuzinamab is a monoclonal antibody that elevates the level of the immune regulatory protein progranulin by blocking sortiline.

Gary: The breakthrough designation that provided the opportunity for increased interactions with the FDA on this program

Gary: And now we have additional clarity on how key biomarkers may support our path to a potential regulatory submission.

Arnon Rosenthal: We will provide more details on this FDA feedback during today's call. Looking ahead, we believe that we are on track for the pivotal phase, three data readouts from the front three trials in late 2025 early 2026, and we plan to share more specifics soon. Enrollment continues in the PROGRESS-AD Global Phase 2 clinical trial of AL-101 for early Alzheimer's disease, with dosing initiated early this year. Like Ratanuzumab, AL-101 elevates progranolin levels but offers a distinct pharmacokinetic and pharmacodynamic profile suitable for broader indications.

Gary: We will provide more details on this FDI feedback during today's call.

Gary: Looking ahead, we believe that we are on track

Gary: Three data readouts from In Front 3 trial in late 2025-early 2026.

Arnon Rosenthal: And we plan to share most specifics soon. And enrollment continues in the progress A.D. Global Phase II clinical trial of AL 101 for early Alzheimer's disease, with dosing initiated early this year. Like Ratanousa Mob, AL 101 elevates programmable in level but offers a distinct pharmacokinetic and pharmacodynamic profile suitable for broader indications.

Gary: And we plan to share more specifics soon.

Gary: Enrollment continues in the PROGRESS-AD Global Phase II clinical trial of AL-101 for early Alzheimer's disease.

Gary: with dosing initiated early this year.

Gary: Like Ratanuzumab, AL-101 elevates progranolin levels but offers a distinct pharmacokinetic and pharmacodynamic profile suitable for broader indications.

Arnon Rosenthal: Furthermore, in June, we introduced electobrancareer ABC, our proprietary blood-brain barrier technology platform. ABC enhances the delivery of therapeutic agents with greater penetration and efficacy at lower doses, with the goal of reducing costs and improving patient outcomes. The introduction of ABC represented significant advancement in our capabilities to address these challenges of drug delivery in all the generative diseases.

Arnon Rosenthal: Furthermore, in June, we introduced Alector Brain Carrier, ABC, our proprietary blood-brain-barrier technology platform. ABC enhances the delivery of therapeutic agents with greater penetration and efficacy at lower doses with the goal of reducing costs and improving patient outcomes.

Gary: Furthermore, in June , we introduced Alector Brain Carrier, ABC, our proprietary blood-brain barrier technology platform.

Gary: ABC enhances the delivery of therapeutic agents with greater penetration and efficacy at lower doses with the goal of reducing costs and improving patient outcomes.

Arnon Rosenthal: The introduction of ABC represents a significant advancement in our capability to address these challenges of drug delivery in neurodegenerative disease. To summarize, we continue advancing genetically validated first-in-class and best-in-class drug candidates for Alzheimer's disease. Frontotemporal Dementia, and other indications. By targeting genetic pathways implicated in neurodegenerative diseases and combining innovative science with emerging technology. We continue to strive for a world where degenerative brain disorders are a relic of the past. At this time, I'll turn the call over to Gary.

Gary: The introduction of ABC represents a significant advancement in our capability to address these challenges of drug delivery in neurodegenerative diseases.

Arnon Rosenthal: To summarize, we continue advancing genetically validated first in class and best in class drug candidates for Alzheimer's disease from the temporal dementia and other indicates. by targeting genetic pathways implicated in all the generative diseases and combining innovative science with emerging technology, we continue to strive for a world where the generative brain disorders are a relic of the past.

Gary: To summarize,

Gary: We continue advancing genetically validated, first-in-class and best-in-class drug candidates for Alzheimer's disease, frontotemporal dementia, and other indications.

Gary: By targeting genetic pathways,

Gary: Implicated in neurodegenerative diseases and combining innovative science with emerging technology

Gary: We continue to strive for a world where degenerative brain disorders are a relic of the past.

Gary Romano: At this time, I'll turn the call over to Gary. Thank you, Arnon. I'm pleased to provide further insights into our later stage, clinical portfolio, focusing on our advancements with AL-002 and our programming and programs. I'll begin with AL-002. As a reminder, our ongoing INVOKE two phase two trial, which was fully enrolled in September 2023, is a randomized double-blind, placebo-controlled common-close study evaluating up to 96 weeks of treatment with AL-002 in 381 participants with early Alzheimer's disease. This trial includes three doses of AL-002, which demonstrated robust target engagement and increased microglial signaling in our phase one study.

Gary Romano: I'm pleased to provide further insights into our later stage clinical portfolio, focusing on our advancements with AL002 and our progranulin program. I'll begin with AL00.

Gary: At this time, I'll turn the call over to Gary.

Gary: Thank you, Arnon. I'm pleased to provide further insights into our later stage clinical portfolio, focusing on our advancements with AL002 and our progranulin programs.

Gary Romano: As a reminder, our ongoing Invoke 2 Phase 2 trial, which was fully enrolled in September 2023, is a randomized, double-blind, placebo-controlled, common close study evaluating up to 96 weeks of treatment with AL002 in 381 participants with early Alzheimer's disease. This trial includes three doses of AL002, which demonstrated robust target engagement and increased microglial signaling in our Phase 1 study. At the Alzheimer's Association International Conference, or AAIC, last week, Alector presented participant baseline characteristics for in-vote. As Arnon mentioned, the baseline clinical assessments confirm enrollment of the intended population of participants with early Alzheimer's.

Gary: I'll begin with AL002.

Gary Romano: The clinical diagnosis at enrollment was mild cognitive impairment due to Alzheimer's disease for 67% of participants and mild dementia due to Alzheimer's disease for 33% of participants. Notably, participants with baseline amyloid assessments demonstrated a mean centelloid level of 100.1, aligning with expectations for an early Alzheimer's disease cohort. This data marks an important milestone in our Global Phase 2 trial, which aims to evaluate the safety and efficacy of AL002 while testing the hypothesis that this first-in-class TREM2 agonist may slow the progression of Alzheimer's. We are on track for the Info2 data readout in the fourth quarter of 2024.

Gary: As a reminder, our ongoing Invoke 2 Phase 2 trial

Gary: which was fully enrolled in September 2023, is a randomized, double-blind, placebo-controlled, common-closed study evaluating up to 96 weeks of treatment with AL002 in 381 participants with early Alzheimer's disease.

Gary: This trial includes three doses of AL002 which demonstrated robust target engagement and increased microglial signaling in our phase one study.

Gary Romano: At the Alzheimer's Association International Conference, or AIC, last week, Alector presented participant baseline characteristics for invoked two. As Arnon mentioned, the baseline clinical assessments confirm enrollment of the intended population of participants with early Alzheimer's disease. The clinical diagnosis at enrollment was mild causative impairment due to Alzheimer's disease for 67% of participants and mild dementia due to Alzheimer's disease for 33% of participants. Notably, participants with baseline amyloid assessments demonstrated a mean centeloid level of 100.1, aligning with expectations for early Alzheimer's disease cohorts. This data marks an important milestone in our global phase two trial, which aims to evaluate the safety and efficacy of AL-002 while testing the hypothesis that this first-in-class trim to agonist may slow the progression of Alzheimer's disease.

Speaker Change: At the Alzheimer's Association International Conference, or AAIC, last week, Alector presented participant baseline characteristics for Invoke 2.

Speaker Change: As Arnon mentioned, the baseline clinical assessments confirm enrollment of the intended population of participants with early Alzheimer's disease.

Speaker Change: is

Arnon Rosenthal: the clinical diagnosis at enrollment was mild positive impairment due to alzheimer'sdisease

Speaker Change: for 67% of participants.

Speaker Change: and mild dementia due to Alzheimer's disease for 33% of participants.

Speaker Change: Notably, participants with baseline amyloid assessments demonstrated a mean centelloid level of 100.1.

Speaker Change: Aligning with Expectations for Early Alzheimer's Disease Cohorts.

Speaker Change: this data marks an important milestone in our global phase i trial which aims to evaluate the safety and efficacy of a zerozer two while testing the hypothesis that this first in-class timps to agonist may slow the progression of alzheimer s disease

Gary Romano: We are on track for the invoked two data readout in the fourth quarter of 2024.

Speaker Change: We are on track for the Info2 data readout in the fourth quarter of 2024.

Gary Romano: Today, I'd like to describe the trial's outcome measures, our statistical analysis approach, our long-term extension study, and the expected trial outcome. We are also collecting secondary clinical and functional outcome assessments, including the ADAS-COG-13 and ADCS-ADL-MCI, from which we will derive treatment effects on the Integrated Alzheimer's Rating Scale, or IDRS. This trial will also deliver a robust biomarker. Assessing Target Engagement, Treatment Effects on Microglia, and Treatment Effects on Alzheimer's Pathophysiology. Target engagement will be assessed by measuring treatment effects on CSF levels of soluble trenches.

Gary Romano: Today, I'd like to describe the trial's outcome measures, our statistical analysis approach, our long-term extension study, and the expected trial outcomes. The primary clinical outcome is the CDR sum of boxes. We are also collecting secondary clinical and functional outcome assessments, including the ASCOG 13 and ADCS ADL MCI, from which we will derive treatment effects on the integrated Alzheimer's rating scale or hydros. This trial will also deliver a robust biomarker package, assessing target engagement, treatment effects on microglia, and treatment effects on Alzheimer's pathophysiology. Target engagement will be assessed by measuring treatment effects on CSF levels of soluble trim too.

Speaker Change: Today, I'd like to describe the trial's outcome measures, our statistical analysis approach, our long-term extension study, and the expected trial outcomes.

Speaker Change: the primary clinical outcome is the cdrr sum of boxes

Speaker Change: We are also collecting secondary clinical and functional outcome assessments, including the ADAS-COG-13 and ADCS-ADL-MCI, from which we will derive treatment effects on the Integrated Alzheimer's Rating Scale, or IDRS.

Speaker Change: This trial will also deliver a robust biomarker package.

Speaker Change: Assessing Target Engagement, Treatment Effects on Microglia, and Treatment Effects on Alzheimer's Pathophysiology.

Speaker Change: Target engagement will be assessed by measuring treatment effects on CSF levels of soluble TREM 2.

Gary Romano: You will recall that in our phase one healthy volunteer study following single doses, we saw dose-dependent reductions in CSF soluble trim. Two, including changes from baseline exceeding 50% at our highest doses. Treatment effects on microglial signaling will be assessed by measuring levels of CSF-1R, STP-1, and IL-1RN, which reflect proliferation, survival, and phagocytic activity of microglia. As previously reported, we saw treatment effects on each of these pathways after single doses in our Phase One study. We are also exploring omics assessments of treatment-regulated changes in microglial subtypes. Treatment effects on Alzheimer's pathophysiology will be assessed with CSF-1 plasma biomarkers with A-beta and tau, as well as both amyloid PET and tau PET.

Gary Romano: You will recall that in our phase one healthy volunteer study following single, we saw dose-dependent reductions in CSF-soluble TREM2, including changes from baseline exceeding 50% at our highest dose. Treatment effects on microglial signaling will be assessed by measuring levels of CSF1R, SPP1, and IL1RN, which reflect proliferation, survival, and phagocytotic activity of microglia. As previously reported, we saw treatment effects on each of these pathways after single doses in our phase one study.

Speaker Change: You will recall that in our Phase 1 Healthy Volunteer Study, following single doses,

Speaker Change: We saw dose-dependent reductions in CSF-soluble TREM2.

Speaker Change: including changes from baseline exceeding 50% at our highest doses.

Speaker Change: Treatment effects on microglial signaling will be assessed by measuring levels of CSF1R, SPP1, and IL1RN, which reflect proliferation, survival, and phagocytotic activity of microglia.

Speaker Change: As previously reported, we saw treatment effects on each of these pathways after single doses in our Phase 1 study.

Gary Romano: We are also exploring omics assessments of treatment-related changes in microglial subtypes. Treatment effects on Alzheimer's pathophysiology will be assessed with CSF and plasma biomarkers for A-beta and tau, as well as both amyloid PET and tau PET. We will also have biomarkers of astrogliosis, neuroinflammation, synaptic health, and neurodegenerative. The Phase 2 Invoke-2 trial utilizes a common closed design in which participants remain in a double-blind study until the last participant completes 48 weeks of treatment. Earlier enrolled participants continue in the double-blind study for a maximum of 96 weeks of treatment before they are invited to join our long We intend to use a proportional analysis approach, or specifically proportional MMRM, which enables us to use all the data collected in this common closed design trial.

Speaker Change: We are also exploring omics assessments of treatment-related changes in microglial subtypes.

Speaker Change: Tumor effects on Alzheimer's pathophysiology will be assessed with CSF and plasma biomarkers of A, beta, and tau.

Gary Romano: We will also have biomarkers with astrogliosis, neuroinflammation, synaptic health, and neurodegeneration. The phase two INVOKE TWO trial utilizes a common closed design in which participants remain in a double-blind study until the last participant completes 48 weeks of treatment. Earlier enrolled participants continue in the double-blind study for a maximum of 96 weeks of treatment before they are invited to join our long-term extension study. We intend to use a proportional analysis approach, or specifically proportional MMORM, which enables us to use all the data collected in this common closed design trial. This means we will include data from all participants out to 48 weeks, and also include additional data provided by the participants who will have had follow-up for up to 96 weeks.

Speaker Change: as well as both amyloid PET and tau PET.

Speaker Change: We will also have biomarkers of astrogliosis, neuroinflammation, synaptic health, and neurodegeneration.

Speaker Change: The Phase 2 Invoke-2 trial utilizes a common closed design in which participants remain in a double-blind study until the last participant completes 48 weeks of treatment.

Speaker Change: Earlier enrolled participants continue in the double blind study for a maximum of 96 weeks of treatment before they are invited to join our long-term extension study.

Speaker Change: We intend to use a proportional analysis approach, or specifically proportional MMRM, which enables us to use all the data collected in this common closed design trial.

Gary Romano: This means we will include data from all participants out to 48 weeks and also include additional data provided by the participants who will have had follow-up for up to 90. Efficacy will be calculated as the average treatment effect observed across multiple post-baseline visits. This approach increases power, potentially enabling us to reach statistical significance at a smaller effect size. If our drug slows disease progression comparable to the treatment effects of the anti-amyloid antibodies, we may observe a significant treatment effect.

Speaker Change: This means we will include data from all participants out to 48 weeks.

Speaker Change: and also include additional data provided by the participants who will have had follow-up for up to 96 weeks.

Gary Romano: Ethnicacy will be calculated as the average treatment effect observed across multiple post-baseline visits. This approach increases power, potentially enabling us to reach statistical significance at a smaller effect size. If our drug slows disease progression comparable to the treatment effects of the anti-amyloid antibodies, we may deserve a significant treatment effect. Our ongoing INVOKE two long-term extension study is currently underway for participants who completed the initial treatment period. This LTE study remains blinded to treatment assignment, allowing for an ongoing collection of meaningful clinical biomarker and safety data. Thus far, approximately 95% of eligible participants from Invoke Two have enrolled in the LTE study.

Speaker Change: Efficacy will be calculated as the average treatment effect observed across multiple post baseline visits.

Speaker Change: This approach increases power, potentially enabling us to reach statistical significance at a smaller effect size.

Speaker Change: If our drug slows disease progression comparable to the treatment effects of the anti-amyloid antibodies, we may observe a significant treatment effect.

Gary Romano: Our ongoing Invoke II long-term extension study is currently underway for participants who completed the initial treatment. This LTE study remains blinded to treatment assignment, allowing for an ongoing collection of meaningful clinical biomarker and safety data. Thus far, approximately 95% of eligible participants from InVoke2 have enrolled in the LTE study.

Speaker Change: Our ongoing Invoke II Long-Term Extension Study is currently underway for participants who completed the initial treatment period.

Speaker Change: This LTE study remains blinded to treatment assignment, allowing for an ongoing collection of meaningful clinical biomarker and safety data.

Speaker Change: Thus far, approximately 95% of eligible participants from InVoke2 have enrolled in the LTE study.

Gary Romano: In this LTE study, we are also assessing the effects of a modified dose titration on the severity of treatment-emergent MRI findings resembling amyloid-revaded imaging abnormalities or area. Participants who roll over from the placebo in the double-blind trial to active treatment in the LTE will begin titration at a lower dose than was used in the double-blind trial. And we'll also have a slower dose titration schedule. This is intended to explore the effects of starting at a lower dose and using slower titration on the observed treatment-revaded MRI findings that resemble ours. For context, in the invoked two double-blind trial, Dosey started at 15 milligrams per kilogram, and dose escalation occurred every four weeks during the first three months of the trial.

Gary Romano: In this LTE study, we are also assessing the effects of a modified dose titration on the severity of treatment emergent MRI findings resembling amyloid-related imaging abnormalities, or ARI. Participants who rollover from the placebo in the double-blind trial to active treatment in the LTE will begin titration at a lower dose than was used in the double-blind trial and will also have a slower This is intended to explore the effects of starting at a lower dose and using slower titration on the observed treatment-related MRI findings that resemble ours. For context, in the INVOKE-2 double-blind trial, dosing started at 15 mg per kg, and dose escalation occurred every four weeks during the first three months of the trial.

Speaker Change: In this LTE study, we are also assessing the effects of a modified dose titration on the severity of treatment emergent MRI findings resembling amyloid-related imaging abnormalities, or ARIA.

Speaker Change: Participants who roll over from the placebo in the double-blind trial to active treatment in the LTE will begin titration at a lower dose than was used in the double-blind trial and will also have a slower dose titration schedule.

Speaker Change: This is intended to explore the effects of starting at a lower dose and using slower titration on the observed treatment-related MRI findings that resemble ARIA.

Speaker Change: For context, in the INVOKE-2 double-blind trial, dosing started at 15 milligrams per kilogram, and dose escalation occurred every four weeks during the first three months of the trial.

Gary Romano: Our hypothesis for the invoked two trial is that treatment with AL-002 will increase trend to signaling, leading to a therapeutic restoration of microglial functions that protect against neurodegenerative disease. This includes the clearance and misfolded proteins such as amyloid, but we also expect AL-002 to amplify the broader beneficial effects of healthy microglia on the brain, such as maintenance of synaptic connections, supportive astrocytin oligodendocyte function, repair and maintenance of the blood-brain barrier, and the vasculature, and regulation of immune tolerance. Thus, our expectation is that restoration of microglial function by AL-002 will reduce the brain's vulnerability to neurodegenerative disease, and that the invoked two trial will demonstrate treatment-revaded slowing of Alzheimer's disease progression, as demonstrated by a combination of clinical, functional, and biomarker readouts.

Gary Romano: Our hypothesis for the INVOKE-2 trial is that treatment with AL002 will increase TREM-2 signaling leading to therapeutic restoration of microglial functions that protect against neurodegenerative disease. This includes the clearance of misfolded proteins such as amyloid. But we also expect AL002 to amplify the broader beneficial effects of healthy microglia on the brain, such as maintenance of synaptic connections. Supportive Astrocyte and the Oligodendrocyte Fund Repair and maintenance of the blood-brain barrier and the BASC, and regulation of immune tolerance

Speaker Change: Our hypothesis for the INVOKE-2 trial is that treatment with AL002 will increase TREM-2 signaling, leading to therapeutic restoration of microglial functions that protect against neurodegenerative disease.

Speaker Change: This includes the clearance of misfolded proteins such as amyloid.

Speaker Change: But we also expect AL002 to amplify the broader beneficial effects of healthy microglia on the brain, such as maintenance of synaptic connections.

Speaker Change: Supportive Astrocyte and Oligodendrocyte Function

Speaker Change: Repair and maintenance of the blood-brain barrier and the vasculature.

Gary Romano: Thus, our expectation is that restoration of microbial function by AL002 will reduce the brain's vulnerability to neurodegenerative disease, and at the Invoke 2 trial, we'll demonstrate treatment-related slowing of Alzheimer's disease progression as demonstrated by a combination of clinical, functional, and biomarker research. With its broad and complementary mechanism of action, we expect AL002 to be effective as a standalone therapy and may also demonstrate additive or synergistic effects when used in combination with other amyloid-targeted therapeutics.

Speaker Change: and Regulation of Immune Tolerance.

Speaker Change: Thus, our expectation is that restoration of microglial function by AL002 will reduce the brain's vulnerability to neurodegenerative disease.

Speaker Change: And that the INVOKE-2 trial will demonstrate treatment-related slowing of Alzheimer's disease progression, as demonstrated by a combination of clinical, functional, and biomarker readouts.

Gary Romano: With its broad and complementary mechanism of action, we expect AL-002 to be effective as a standalone therapy and may also demonstrate additive or synergistic effects when used in combination with amyloid-targeted therapeutics. We also believe that treatment benefits of AL-002 may manifest differently from what we have seen in trials of the anti-amyloid antibodies. For example, with regard to biomarker responses, lowering cerebral amyloid PET signal to the 24-centraloid threshold, which for anti-amyloid antibodies appears to be a necessary condition for clinical efficacy, may not be relevant to this mechanism of action that goes beyond amyloid clearance. Additionally, optimal disease stages for intervention may be broader.

Speaker Change: With its broad and complementary mechanism of action, we expect AL002 to be effective as a standalone therapy and may also demonstrate additive or synergistic effects when used in combination with amyloid-targeted therapeutics.

Gary Romano: We also believe that treatment benefits of AL002 may manifest differently from what we have seen in trials of the anti-amyloid antibody. For example, with regard to biomarker responses, lowering the cerebral amyloid PET signal to the 24 centiloid, which for anti-amyloid antibodies appears to be a necessary condition for clinical efficacy, may not be relevant to this mechanism of action that goes beyond amyloid clearance. Additionally, optimal disease stages for intervention may be broader.

Speaker Change: We also believe that treatment benefits of AL002 may manifest differently from what we have seen in trials of the anti-amyloid antibodies.

Speaker Change: For example, with regard to biomarker responses, lowering cerebral amyloid PET signal to the 24 centiloid threshold

Speaker Change: which for anti-amyloid antibodies appears to be a necessary condition for clinical efficacy.

Speaker Change: may not be relevant to this mechanism of action that goes beyond amyloid clearance.

Gary Romano: Unlike therapeutics targeting amyloid or tau, we do not expect the beneficial effects of healthy microglia to be limited to specific pathophysiological stages of disease. Thus, AL-002 may have potential to benefit patients ranging from pre-clinical Alzheimer's disease through advanced dementia.

Speaker Change: Additionally, optimal disease stages for intervention may be broader. Unlike therapeutics targeting amyloid or tau, we do not expect the beneficial effects of healthy microglia to be limited to specific pathophysiological stages of disease.

Gary Romano: Unlike therapeutics targeting amyloid or tau, we do not expect the beneficial effects of healthy microglia to be limited to specific pathophysiological stages of disease. Thus, AL002 may have potential to benefit patients ranging from preclinical Alzheimer's disease through advanced dementia. Now, we turn to our ProGranulon program.

Speaker Change: Thus, AL002 may have potential to benefit patients ranging from preclinical Alzheimer's disease through advanced dementia.

Gary Romano: Turning now to our program. In a recent type of interaction with the FDA, we in GSK received feedback on the potential future Biologics License Application for LATASINIMAP. The FDA has indicated that it would consider the effects of LATASINIMAP on plasma and cerebral spinal fluid, with progranoline levels, as confirmatory evidence, supplementing the potential clinical effects of LATASINIMAP, pending BLA review. We also aligned with the agency on disease-relevant fluid and imaging biomarkers that may be considered a supportive evidence of clinical efficacy, also subject to BLA review. These include biomarkers of astrocyte function, neurodegeneration, and brain access.

Gary Romano: In a recent Type B interaction with the FDA, we at GSK received feedback on the potential future biologics license application for latizinumab. The FDA has indicated that it would consider the effects of laticinamide on plasma and cerebrospinal fluid progranulin levels as confirmatory evidence, supplementing the potential clinical effects of laticinamide pending BLA review. We also aligned with the Agency on Disease-Relevant Fluid and Imaging Biomarkers, which may be considered supportive evidence of clinical efficacy, also subject to BLA review.

Speaker Change: Turning now to our ProGranulon programs.

Speaker Change: In a recent Type B interaction with the FDA,

Speaker Change: We in GSK received feedback on the potential future biologics license application for latazinamab.

Speaker Change: The FDA has indicated that it would consider the effects of laticinimab on plasma and cerebrospinal fluid progranulin levels as confirmatory evidence.

Speaker Change: Supplementing the potential clinical effects of laticinamide.

Speaker Change: Pending BLA review.

Speaker Change: We also aligned with the Agency on Disease-Relevant Fluid and Imaging Biomarkers.

Speaker Change: and others that may be considered as supportive evidence of clinical efficacy.

Gary Romano: These include biomarkers of astrocyte function, neurodegeneration, and brain atrophy. Based on FDA feedback, we remain confident that the totality of evidence, including the primary clinical endpoint and biomarkers, could provide a path to potential approval for Latos Unimax. Following these productive interactions with the FDA, we believe we are on track for the pivotal front three phase three data readout in late 2025 or early 2026. In parallel, enrollment continues in the PROGRESS-AD Global Phase II Clinical Trial of AL101 for early Alzheimer's.

Speaker Change: Also subject to BLA review.

Speaker Change: These include biomarkers of astrocyte function, neurodegeneration, and brain atrophy.

Gary Romano: on the FDA feedback. We remain confident that the totality of evidence, including the primary clinical endpoints and biomarkers, could provide a path to potential approval for ladders in a map. Following these productive interactions with the FDA, we believe we are on track for the pivotal in front three phase three data readout in late 2025 or early 2026. In parallel, enrollment can be continued in the progress AD global phase two clinical trial of AL 101 for early Alzheimer's disease. We and GSK are co-developing AL 101 for the potential treatment of more prevalent neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.

Speaker Change: Based on the FDA feedback, we remain confident that the totality of evidence

Speaker Change: including the primary clinical endpoint and biomarkers.

Speaker Change: could provide a path to potential approval for provos internet

Speaker Change: Following these productive interactions with the FDA, we believe we are on track for the pivotal InFront3 Phase 3 data readout in late 2025 or early 2026.

Speaker Change: Thank you very much.

Speaker Change: In parallel, enrollment continues in the PROGRESS-AD Global Phase II Clinical Trial of AL-101 for Early Alzheimer's Disease.

Gary Romano: We and GSK are co-developing AL-101 for the potential treatment of more prevalent neurodegenerative diseases, including Alzheimer's disease and Parkinson's. At AAIC, our partner GSK presented a poster highlighting data supporting the hypothesis that therapeutic increases of progranulin levels may be an effective treatment for Alzheimer's disease. These findings demonstrate consistent causal associations between increased progranulin levels and reduced Alzheimer's disease, across the progranulin gene, as you would expect, providing compelling genetic evidence for increasing progranulin levels as a potential therapeutic strategy to treat As we advance these programs, we remain dedicated to harnessing our scientific and clinical expertise to drive forward transformative therapies for neurodegenerative diseases.

Speaker Change: We and GSK are co-developing AL-101 for the potential treatment of more prevalent neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.

Gary Romano: At AAC, our partner GSK presented a poster highlighting data supporting the hypothesis that therapeutic increases of the pergranular levels may be an effective treatment for Alzheimer's disease. These findings demonstrate consistent causal associations between increased pergranular levels and reduced Alzheimer's disease risk across the pergranular gene oelic spectrum, providing compelling genetic evidence for increasing pergranular levels as a potential therapeutic strategy to treat Alzheimer's disease. As we advanced these programs, we remain dedicated to harnessing our scientific and clinical expertise to drive forward transformative therapies for neurodegenerative diseases.

Speaker Change: at aic our partner gk presented a poster highlighting data supporting the hypothesis that therapeutic increases of prograndulum levels may be an affected treatment for alzheimer's disease

Speaker Change: These findings demonstrate consistent causal associations between increased progranulone levels and reduced Alzheimer's disease risk across the progranulone gene-alveolic spectrum.

Speaker Change: Providing compelling genetic evidence for increasing progranulin levels as a potential therapeutic strategy to treat Alzheimer's disease.

Speaker Change: As we advance these programs,

Speaker Change: We remain dedicated to harnessing our scientific and clinical expertise to drive forward transformative therapies for neurodegenerative diseases.

Sara Kenkare: At this time, I'll turn it over to Sarah for updates on our progress with the Electoral Brain Carrier. Thank you, Gary. In June, we held a virtual R&D event highlighting our Electoral Brain Carrier Blood Brain Barrier Technology Platform. At Electoral, we've dedicated several years to developing our proprietary world style Electoral Brain Carrier Technology known as ABC. We are leveraging the ABC platforms as a vital tool in our preclinical pipelines and novel drug development. ABC enables us to expand our pipeline to include neurodegenerative diseases requiring enzyme or protein replacement. It enhances our novel antibody pipeline by improving brain distribution, potentially requiring lower doses and enabling subcutaneous delivery.

Speaker Change: At this time, I'll turn it over to Sara for updates on our progress with the electro-brain carrier.

Sara Kenkare: In June, we held a virtual R&D event highlighting our Alector Brain Carrier Blood-Brain Barrier Technology platform. At Alector, we've dedicated several years to developing our proprietary, versatile Alector Brain Carrier technology, known as ABR.

Sarah: Thank you, Danny.

Sarah: In June , we held a virtual R&D event highlighting our Alector Brain Carrier blood-brain barrier technology platform.

Sarah: At Alector, we've dedicated several years to developing our proprietary, versatile electro-brain carrier technology known as ABC.

Sara Kenkare: We are leveraging the ABC platform as a vital tool in our preclinical pipeline and novel drug development. ABC enables us to expand our pipeline to include neurodegenerative diseases requiring enzyme or protein replacement. It enhances our novel antibody pipeline by improving brain distribution, potentially requiring lower doses, and enabling subcutaneous delivery. Additionally, we are also leveraging our ABC technology in the development of second generation drugs toward our pipeline and validated targets.

Sarah: We are leveraging the ABC platform as a vital tool in our preclinical pipeline and novel drug development.

Speaker Change: ABC enables us to expand our pipeline to include neurodegenerative diseases requiring enzyme or protein replacement.

Sarah: It enhances our novel antibody pipeline by improving brain distribution, potentially requiring lower doses, and enabling subcutaneous delivery.

Sara Kenkare: Additionally, we're also leveraging our ABC technology in the development of second-generation drugs towards our pipeline and validated targets. ABC has been validated with multiple therapeutic cargoes. Notably, we've focused on two key transporting targets, transfer and receptor known as TFR and CD98 heavy chains. TFR, a well-known ion transport receptor, swiftly delivers cargo to the endolysis-omal system, while CD98 heavy chains integrals to amino acid transport complexes targets cargo primarily across the endocardial cell surface. Both receptors enable effective delivery of functional cargoes, including antibodies and... Dr. Protoons to target itself within the central nervous system. Having multiple receptor targets allows us to tailor brain uptake, optimizing efficacy and safety.

Sarah: Additionally, we are also leveraging our ABC technology in the development of second generation drugs towards our pipelined and validated targets.

Sara Kenkare: ABC has been validated with multiple therapeutic cargoes. Notably, we've focused on two key transporting targets, transparent receptor known as TFR and CD98 heavy. TFR, a well-known ion transport receptor, swiftly delivers cargo to the endolysosomal system, while CD98 heavy chain, integral to amino acid transport complexes, targets cargo primarily across the endothelial cell surface.

Speaker Change: ABC has been validated with multiple therapeutic cargoes. Notably, we've focused on two key transporting targets, transferrin receptor, known as TFR, and CD98 heavy chain.

Speaker Change: TFR, a well-known ion transport receptor, swiftly delivers cargo to the endolysosomal system, while CD98 heavy chain integral to amino acid transport complexes targets cargo primarily across the endothelial cell surface.

Sara Kenkare: Both receptors enable effective delivery of functional cargoes, including antibodies and proteins, to targeted cells within the central nervous system. Having multiple receptor targets allows us to tailor brain uptake, optimizing efficacy and safety. Our approach with ABC is distinguished by its versatility, tunability, and translatability. Our ABC technology is versatile and can accommodate a wide range of cargoes, from antibodies to nucleic acids, thus enhancing its application across neurodegenerative diseases. Tunability is core to our technology, utilizing a diverse panel of binders with varying affinities to blood-brain barrier receptors to precisely match different cargoes, optimizing therapeutic efficacy while ensuring safety.

Sarah: Both receptors enable effective delivery of functional cargos, including antibodies and proteins, to targeted cells within the central nervous system.

Speaker Change: Having multiple receptor targets allows us to tailor brain uptake, optimizing efficacy and safety.

Sara Kenkare: Our approach with ABC is distinguished by its versatility, tunability, and translitability. Our ABC technology is versatile and can accommodate a wide range of cargos, from antibodies to nucleic acids, thus enhancing its application across neurodegenerative diseases. Tunability is called to our technology, utilizing a diverse panel of binders with varying affinities to blood-brain barrier receptors to precisely match different cargos, optimizing therapeutic efficacy while ensuring safety. Additionally, translitability from pre-clinical to clinical species is a key feature and can be important in accelerating our path to clinical trials, ultimately enabling sufficient delivery of innovative treatments to patients. ABC's capabilities underscore electron commitment to advancing therapies for neurodegenerative diseases by overcoming challenges in drug delivery to the brain, positioning us at the forefront of neurodegenerative disease drug development.

Sarah: Our approach with ABC is distinguished by its versatility, tunability, and translatability.

Sarah: Our ABC technology is versatile and can accommodate a wide range of cargoes, from antibodies to nucleic acids, thus enhancing its application across neurodegenerative diseases.

Sarah: Tunability is core to our technology, utilizing a diverse panel of binders with varying affinities to blood-brain barrier receptors to precisely match different cargoes, optimizing therapeutic efficacy while ensuring safety.

Sarah: Additionally, translatability from preclinical to clinical species is a key feature and can be important in accelerating our path to clinical trials, ultimately enabling efficient delivery of innovative treatments to patients.

Sara Kenkare: Additionally, translatability from preclinical to clinical species is a key feature and can be important in accelerating our path to clinical trials, ultimately enabling efficient delivery of innovative treatments to patients. ABC's capabilities underscore Alector's commitment to advancing therapies for neurodegenerative diseases by overcoming challenges in drug delivery to the brain, positioning us at the forefront of neurodegenerative disease drug development. Looking ahead, we will continue to provide updates on our ABC programs as they progress, reinforcing our dedication to pioneering new frontiers in brain research. Now, I'll turn the call over to Marc for an update on our financial results and milestone updates.

Speaker Change: ABC's capabilities underscore Alecto's commitment to advancing therapies for neurodegenerative diseases by overcoming challenges in drug delivery to the brain, positioning us at the forefront of neurodegenerative disease drug development.

Sara Kenkare: Looking ahead, we will continue to provide updates on our ABC programs as they progress, reinforcing our dedication to pioneering new frontiers in brain health.

Sarah: Looking ahead, we will continue to provide updates on our ABC programs as they progress, reinforcing our dedication to pioneering new frontiers in brain health.

Marc Grasso: Now, I'll turn the call over to Mark for an update on our financial results and milestone outcomes. Thank you, Sarah. We summarized our second quarter of 2024 financial results and the press release that we made available after the market closed today. First, I'll highlight that we remain well-funded to execute our strategic objectives. We ended the second quarter of 2024 with a strong cash position of $503.3 million.

Sarah: Now, I'll turn the call over to Marc for an update on our financial results and milestone algorithm.

Marc Grasso: Thank you, Sara. We summarized our second quarter 2024 financial results in the press release we made available after the market closed today. First, I'll highlight that we remain well funded to execute our strategic objective. We ended the second quarter of 2024 with a strong cash position of $503.3 million. Our cash runway extends through 2026, demonstrating robust financial preparedness for future growth and financial strength through the completion of key milestones, including the AL002 Invoke 2 Phase 2 data readout and the Pivotal InFront 3 Phase 3 data readout for Leda Zinomad, with the runway coverage extending approximately a year beyond the InFront 3 readout.

Marc: Thank you, Sara. We summarized our second quarter 2024 financial results in the press release we made available after the market closed today.

Marc: First, I'll highlight that we remain well-funded to execute our strategic objectives.

Marc: We ended the second quarter of 2024 with a strong cash position of $503.3 million.

Marc Grasso: Our cash runway extends through 2026, demonstrating robust financial preparedness for future growth and financial strength through the completion of key milestones, including the AL-002 invoked to Phase 2 data readout, and the pivotal in-front three Phase 3 data readout for letters in a map, with the runway coverage extending approximately a year beyond the in-front three readout. Turning now to 2024 financial guidance, we continue to anticipate collaboration revenue to be between $60 million and $70 million. We have tightened our total research and development guidance to be between $210 million and $220 million. We have reiterated our total general and administrative guidance to be between $60 million and $70 million.

Marc: Our cash runway extends through 2026, demonstrating robust financial preparedness for future growth and financial strength through the completion of key milestones, including the AL002 Invoke 2 Phase 2 data readout and the pivotal InFront3 Phase 3 data readout for Leta Zinemab.

Sarah: With the runway coverage extending approximately a year beyond the In Front 3 readout.

Marc Grasso: Turning now to 2024 financial guidance, we continue to anticipate collaboration revenue between $60 million and $70 million. We have tightened our total research and development guidance to be between $210 million and $220 million. We have reiterated our total general and administrative guidance to be between $60 million and $70 million. We are well capitalized with a robust cash position and remain focused on advancing our later stage and ABC Portfolio. 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.

Marc: Turning now to 2024 Financial Guidance.

Speaker Change: We continue to anticipate collaboration revenue to be between $60 million and $70 million.

Marc: We have tightened our total research and development guidance to be between $210 million and $220 million. We have reiterated our total general and administrative guidance to be between $60 million and $70 million.

Marc Grasso: We are well-capitalized for the robust cash position and remain focused on advancing our later stage and ABC portfolio. We look forward to providing additional updates as we progress our work.

Marc: We are well capitalized with a robust cash position and remain focused on advancing our later stage

Sarah: and ABC Portfolio. We look forward to providing additional updates as we progress our work.

Marc Grasso: That concludes our prepared comments for today's call.

Operator: Operator, you may now open the line for questions. Thank you. At this time, we will conduct the question-and-answer session.

Speaker Change: That concludes our prepared comments for today's call. Operator, you may now open the line for questions.

Operator: Thank you. At this time, we will conduct the question and answer session. As a reminder, to ask a question, you'll need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A list. And our first question comes from Paul Matisse with Stiefel.

Operator: As a reminder, to ask the question, you'll need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster.

Speaker Change: Thank you. At this time, we will conduct the question and answer session. As a reminder, to ask a question, you'll need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster.

Julian Pino: And our first question comes from Paul Matisse with Steffel. Hi there. This is Julian on for Paul. Thanks so much for taking our question.

Marc: And our first question comes from Paul Matisse with Stiefel.

Julian: Hi there. This is Julian on behalf of Paul.

Julian Pino: So a couple from me on on trend to do you mind just reminding everybody what proportion of data from participants out to 48 weeks and 96 weeks and somewhere in between. You expect in this upcoming readout, and also do you plan on rolling over eight POE for homozygotes that were in the placebo group to your long-term extension study. And then also on loud as in a mad. Can you just clarify what exactly does it mean that the FDA would consider plasma and CSS PDRN as confirmatory. I guess to me it seems a little unusual as biomarkers for a biomarker to be confirmatory evidence of clinical benefit.

Julian: Thanks so much for taking our questions. So, a couple from me. On TREM2, do you mind just reminding everybody what proportion of data from participants out to 48 weeks and 96 weeks and somewhere in between you expect in this upcoming readout? And also, do you plan on rolling over APOE4 homozygotes that were in the placebo group into your long-term extension study? And then also on latizinumab, can you just clarify what exactly it means that the FDA would consider plasma and CSF-PGRN as confirmatory?

Speaker Change: Hi there, this is Julian on for Paul. Thanks so much for taking our question.

Julian: So, a couple from me. On trend two, do you mind just reminding everybody...

Speaker Change: What proportion of data from participants out to 48 weeks and 96 weeks and somewhere in between

Speaker Change: Do you plan on rolling over APOE4 homozygotes that were in the placebo group to your long-term extension study? And then also on latizinumab.

Julian: I guess, to me, it seems a little unusual for biomarkers to be confirmatory evidence of clinical benefit. Usually, it's, you know, predicting clinical benefit in the absence of clinical data. So, any additional color would be really helpful there. Thank you.

Speaker Change: can you just clarify what exactly does it mean that the f d a would consider a plasma c s s p g r n as confirmatory i guess to me it seems a little unusual as biomarkers

Gary Romano: Usually it's predicting clinical benefit in the absence of clinical data. So any additional color would be really helpful there. Thank you.

Gary Romano: Hi, this is Gary. I can take that. So I think your first question was around TREM 2. What How many patients do we have at the different time points? So all of the patients, all the completers, which we expect to be around 250, will complete 48 weeks of treatment. And then we'll have about half of those, and we'll have 72 weeks of treatment. And about a third, we'll have 96 weeks of treatment. And I want to just remind you that our LTE remains blinded to original treatment assignment, which means that we'll still be having to be able to Collection of Related Work, A couple of thoughts.

Gary Romano: This is Gary. I can take that. So I think your first question was around trend to what is the how many patients that we have at the different time points. So all of the patients, all the completers, which we expect to be around 250, will complete 48 weeks of treatment. And then we'll have about half of those will have 72 weeks of treatment, and about a third will have 96 weeks treatment. And I want to just remind you that our LTE remains blinded to original treatment assignment, which means that we'll still be getting to be able to collect meaningful data on biomarkers and safety, but also on clinical outcomes given the blindness.

Gary Romano: And the fact that the and that will be up, so six months later we'll have a minimum of 72 weeks of data on all patients, and then six months later, two years of data. Your second question was about the LTE I think about rollover of ApoE homozygotes. No, we are rolling over the placebo group, which is, like the rest of the study, at the current study population does not include APOE4 homozygotes anymore. They were we stopped enrollment early in this study and just discontinued them because we saw more severe MRI changes resembling area in the ApoE for homozygates.

Speaker Change: And then when we got six months later, we will have a minimum of 72 weeks of data on all patients and then six months later two years of data.

Gary Romano: About the LTE, I think about rollover systems for ApoE homozygotes. No, we are rolling over the placebo group, which, like the rest of the study, the current study population does not include ApoE4 homozygotes anymore. They were We stopped enrollment early in this study and discontinued them because we saw more severe MRI changes resembling ARIA in the ApoE4 homozygotes, so they are not rolling over in the LTE.

Speaker Change: Your second question was about the LCD I think about rollover.

Speaker Change: <unk>.

Speaker Change: Homozygous.

Speaker Change: No as we are rolling over the placebo group, which is like the rest of the study at the current study population.

Speaker Change: Does not include <unk> for homozygous anymore. They were so we stopped enrollment early in this study and discontinue them because we saw more severe.

Speaker Change: MRI changes or assembly area in the April for homozygous. So they are not rolling over in the LTE.

Gary Romano: So they are not rolling over in the LTE. And I think your last question was about lattice in a map. What does it mean to be confirmatory evidence of clinical benefit. It means that, you know, if we have a clinically, you know, a positive result on the clinical primary clinical outcome measure, which is the CDR, that the CDR FPD, FLD, NAC, you know, it's the basically a CDR with two additional modules for behavior and language difficulties, which FDA patients have. And what it means is that, you know, we discussed some specifics about some of the biomarkers, imaging and fluid biomarkers that we would use, including a GFAP and an FL and region of interest biometric or biometric MRI.

Gary Romano: And I think your last question was about latizumab. What does it mean to be confirmatory evidence of clinical benefit? It means that, you know, if we have a clinically, clinically, a positive result on the clinical, primary clinical outcome measure, which is the CDR, that the CDR, FDD, FDLD, NAC, it's basically a CDR with two additional modules for behavior and language difficulties which FDD patients have. And what it means is that, you know, we discussed some specifics about some of the biomarkers, imaging, and fluid biomarkers that we would use, including GFAP and NFL and region of interest biometric, or should you say biometric MRI, that they would be considered; if we were to see effects on those biomarkers, that would be added, added, you know, confirmatory evidence of the effect on the clinical outcome measure.

Speaker Change: And I think your last question was about <unk>, what does it mean to be confirmatory evidence of clinical benefit.

Speaker Change: It means that.

Speaker Change: We have a clinical clinically.

Speaker Change: A positive result on the clinical primary clinical outcome measure, which is the CVR.

Speaker Change: That the CVR.

Speaker Change: <unk> now.

Speaker Change: <unk>.

Speaker Change: Basically a CVR with two additional modules for behavior and.

Speaker Change: Language difficulties, which FDA FTB patients have and what it means is that.

Speaker Change: <unk> discussed some some specifics about some of the Biomarkers imaging and fluid biomarkers that we would use including.

Speaker Change: G fast and NFL and.

Speaker Change: <unk> <unk> of interest, while I mentioned, which is to say volumetric MRI.

Gary Romano: It does not mean, in this context, that the biomarkers would be surrogates for, for the clinical outcome measure. However, that said, I mean, we are also fully cognizant that there are many similarities here in FTD to drugs like Taversin that were approved based on an accelerated approval based on some of the same biomarkers, NFL predominantly. And likewise, in this study, we see these biomarkers are prognostic, and FDA, we had a discussion about this about the similarities. And so.

Gary Romano: that they would be, if we were to see effects on those biomarkers, that would be added confirmatory evidence of the effect on the clinical outcome measure. It does not mean in this context that the biomarkers would be surrogates for the clinical outcome measure. However, that said, we are also fully cognizant that there are many similarities here in FTD to drug symptoms, like to a person that was approved based on an accelerated approval based on some of the same biomarkers, NFL predominantly. Likewise, in this study, we see these biomarkers are prognostic and FDA. We had a discussion with this about the similarities.

Speaker Change: That they would be.

Speaker Change: If we already see effects on those biomarkers that would be.

Speaker Change: Added added.

Speaker Change: Confirmatory evidence of the of the effect on the clinical outcome measure it does not mean in this context.

Speaker Change: It would be.

Speaker Change: The biomarkers would be surrogates for for the clinical outcome measure. However that said I mean, we are also fully cognizant that.

Speaker Change: There are there are many similarities here in FTE.

Speaker Change: Two drugs like the person that was approved based on an accelerated approval based on some.

Speaker Change: Some of the same biomarkers NFL predominantly.

Speaker Change: Likewise in this in this study.

Speaker Change: We see these these biomarkers are prognostic.

Speaker Change: And.

Speaker Change: FDA.

Speaker Change: We had a discussion with us about those similarities and so.

Julian Pino: And so, you know, if our, for some reason, we don't expect this, but if, especially based on our phase two data, which is very promising, we expect that if we did, if we weren't disappointed by the clinical outcome, but we saw directional effects. I mean, we think that a backup strategy could be an accelerated approval approach. We have not discussed that with FDA yet, but I think that they're. We're, you know, we're, we're encouraged by their endorsements of the biomarkers that we suggested. That makes sense. Thanks. Appreciate it.

Gary Romano: You know, if, for some reason, and we don't expect this, but if, especially based on our phase two data, which was very promising, we expect that if we did, if we were disappointed by the clinical outcome, but we saw directional effects, I mean, we think that a backup strategy could be an accelerated approval approach. We have not discussed that with FDA yet. But I think that there We're encouraged by their endorsement of the biomarkers that we suggest.

Speaker Change: Yes, yes.

Speaker Change: For some reason and we don't expect this but if.

Speaker Change: Especially based on our phase II data, which is very promising.

Speaker Change: We expect that if.

Speaker Change: If we did if we werent disappointed by the clinical outcome, but we saw directional effects I mean, we think that a backup strategy could be.

Speaker Change: An accelerated approval approach, we have not discussed that with FDA, yet, but I think that there.

Speaker Change: We're encouraged by their by there.

Speaker Change: Endorsements of the Biomarkers that we suggested.

Julian: Got it. It makes sense. Thanks. I appreciate it.

Speaker Change: Got it makes sense. Thanks appreciate it.

Susan: One moment for our next question. And our next question comes from Alex Tranahan with Bank of America.

Susan: One moment for our next question, and our next question comes from Alex Stranahan with Bank of America. Hi, this is Susan on behalf of Alex. He had a question about InVoke2. How should we be thinking about patients enrolling in a long-term extension study for InVoke2 in terms of tolerability and efficacy? Yeah, thank you, Susan.

Speaker Change: One moment for our next question.

Speaker Change: And our next question comes from Alex Stranahan with Bank of America.

Susan: Hi, this is Susan on for Alec. He had a question about invoked you. How should we be thinking about patients enrolling in the long term extension study for invoked you in terms of tolerability and efficacy? Yeah, thank you, Susan. So how do we think about patients enrolling in LTT around efficacy and safety? Well, first, I have to tell you that we're very pleased by the fact that. Up to this point, 95% of patients that have been eligible to roll over, and that's most of the patients by far, have decided to do so and are now in the LTE.

Speaker Change: Hi, This is Susan on for Alex.

Speaker Change: He had a question about in the Q.

Speaker Change: Should we be thinking about patients enrolling in the long term extension study for <unk> in terms of Tolerability and efficacy.

Gary Romano: So how do we think about patients enrolling in LTT around efficacy and safety? Well, first, I have to tell you that we're very pleased by the fact that, up to this point, 95% of patients that have been eligible to roll over, and that's most of the patients by far, have decided to do so and are now in LTE. Some have actually even completed the LTE. And in terms of, you know, efficacy, we will be, you know, we don't know, we're still blinded.

Speaker Change: Yes, Thank you Susan.

Speaker Change: No.

Speaker Change: How do we think about patients enrolling in OTT around efficacy and safety.

Speaker Change: First I have to tell you that we're very pleased by the fact that.

Speaker Change: Up to this point.

Speaker Change: 95% of patients that are ineligible to two rollover and.

Speaker Change: And Thats most of the patients by far.

Speaker Change: Have decided to do so and are now in the LTE.

Gary Romano: Some of actually we completed the LTE. And in terms of, you know, efficacy, we will be, you know, we don't know; we're still blinded, and we will, we haven't looked at efficacy. We will include some of the LTE data that will have been collected up to that time in our sensitivity analysis is the time later this year when we, when we lock the database and have a look at the data. With regard to safety, you know, there really haven't been any significant safety signals beyond the, you know, the MRI signal that was that in resembles area, which we've described in a lot of detail.

Speaker Change: Actually we completed the LT.

Speaker Change: And in terms of.

Gary Romano: And we will, we haven't looked at efficacy, we will include some of the LTE data that will have been collected up to that time in our sensitivity analysis at the time later this year when we lock the database and have a look at the data. With regard to safety, you know, there really haven't been any significant safety signals beyond the, you know, the MRI signal that resembles an area, which we've described in a lot of detail and also, you know, a small number of infusion reactions, which is not to be unexpected with a monoclonal antibody.

Speaker Change: Efficacy.

Speaker Change: We will be we don't know we are still blinded and we havent looked at efficacy. We will include some of the LTE data.

Speaker Change: That will be I've had been collected up to that time in our sensitivity analysis as to time.

Speaker Change: Later this year when we when we.

Speaker Change: Lock the database.

Speaker Change: Look at the data.

Speaker Change: With regard to safety.

Speaker Change: There really haven't been any significant safety signals beyond the.

Speaker Change: The.

Speaker Change: MRI signal.

Speaker Change: Assembles area, which we've described in a lot of detail and.

Gary Romano: And, and also, you know, as a small number of infusion reactions, which is not to be unexpected with a monoclonal antibody.

Speaker Change: And also.

Speaker Change: A small number of infusion reactions, which is not to be unexpected monoclonal.

Speaker Change: Monoclonal antibody.

Susan: Thank you, too.

Sue: Thank you Sue.

Operator: Operator, I think we're ready for the next question.

Michael Riad: Operating, we're ready for the next question. One moment for our next question. Our next question comes from Jeffrey Hung with Morgan Stanley.

Speaker Change: Operator, we're ready for the next question.

Operator: One moment for our next question. The next question comes from Jeffrey Hung with Morgan Stanley.

Speaker Change: Okay.

Speaker Change: One moment for our next question.

Speaker Change: And our next question comes from Jeffrey hung with Morgan Stanley.

Michael Riad: Hi, this is Michael Riad through Jeff Hung. Thank you for taking our question. Going back to the baseline and vote data, so two thirds had mild cognitive impairment and the third had mild dementia. But you also saw a mean and more like pet centawards of around 100 baseline. Are you able to say whether that differed between the two populations in terms of cognitive impairment versus dementia? And also it's not a full capture of the total trial population. Is that something that will get resolved? Thanks, and I have a follow-up. Yeah, so I can't tell you; I don't, we don't have the data broken down by the MCI and mild AD regarding the centawards levels.

Michael Riad: Hi, this is Michael Riad. I'm on behalf of Jeff Hung.

Michael <unk>: Hi, This is Michael <unk> on for Geoff Hoon. Thank you for taking our question.

Michael Riad: Thank you for taking our questions. Going back to the baseline data, so two-thirds had mild cognitive impairment, and the third had mild dementia. But you also saw mean and more like PET sensoloids of around 100 baseline. Are you able to say whether that differed between the two populations in terms of cognitive impairment versus dementia? And also, it's not a full capture of the total trial population. Is that something that will get resolved? Thanks, and I have a follow-up question.

Speaker Change: Going back to the baseline in both data. So two thirds had mild cognitive impairment and third had mild dementia. You also saw mean amyloid pet centralized of around 100 at baseline.

Speaker Change: Are you able to say whether that differed between the two populations in terms of cognitive impairment versus dementia and also a full capture that total trial population is that something that will get resolved.

Speaker Change: Have a followup.

Speaker Change: Yes so.

Gary Romano: I can't tell you, I don't, we don't have the data broken down by the MCI and MILD-AD regarding the centroid levels. I don't, I don't have that. We just looked at the aggregate of centroid levels. And, and, did I miss your other question? I didn't catch the question about full capture; I didn't quite follow what you were asking.

Speaker Change: Yes.

Speaker Change: I can't tell you I don't we don't have the data broken down by the.

Speaker Change: Mci and.

Speaker Change: And mild mild.

Speaker Change: Regarding the central governance, I don't I don't have that.

Michael Riad: I don't have that. We just looked at the aggregate of centawards levels. And you know, we see if I'm just your other question. I didn't catch the question about full capture. I didn't quite follow what you were asking. Oh, sorry about that. I just meant like I thought I was like in the low to like mid 200, and the child had a little more patience. I like is mean M like pet at baseline something that would be captured through the whole population or just the like the 244? Yeah, so we at the this was baseline characteristics.

Speaker Change: We just looked at the aggregate salary levels and.

Speaker Change: And we.

Speaker Change: Did I Miss your other question.

Speaker Change: Focus I didn't catch the question about full capture I did quite well.

Michael Riad: Sorry about that. I just thought it was in the mid-200s and the child had enrolled more patients. Is mean amyloid PET at baseline something that would be captured for the whole population or just the 244?

Speaker Change: Sorry, but I just not I thought it was like in the low to mid two hundreds in the childhood enrolled more patients.

Speaker Change: Mean amyloid pet at baseline something that would be captured through the whole population or just.

Speaker Change: I think the 244.

Gary Romano: Yeah, so we at the This was baseline characteristics. So this was just what we reported out on was the number of patients that were where the patients that had used amyloid PET for inclusion had a baseline amyloid PET scan. So that would include, you know, everyone up to that point for which we had data at that time, which would be everyone because they were fully enrolled.

Speaker Change: Yes so.

Speaker Change: At the.

Gary Romano: Yeah, so, that's, I hope that that answers your question. Yeah, no, that's very helpful. And then just as a quick follow-up, like, what sort of follow-up would you think is the expectations for amyloid reduction and inhibition? That's a good question.

Speaker Change: This was baseline characteristics. So this was just where we.

Michael Riad: So this was just was what we reported out on was the number of patients that was where the patients that had used amyloid PET for inclusion and therefore had a baseline amyloid PET scan. So that would include you know everyone up to that point for which we had data, which would be everyone because of a fully enrolled. Yeah, so that's the hope that that answers your question. Yeah, no, that's very helpful. And then that just was a quick follow-on, like what sort of follow-up. What would you think is the expectations for satellite reduction and then Vogue?

Speaker Change: We reported out on what's the number of patients that are the patients that had used amyloid pet score inclusion and therefore had a baseline amyloid pet scan so that would include.

Speaker Change: We went up to that point.

Speaker Change: For which we have data.

Speaker Change: Which would be everyone because we have a fully enrolled.

Speaker Change: Yeah. So so that's that's.

Speaker Change: I hope this I hope this answers your question.

Speaker Change: And then just as a quick follow on.

Speaker Change: Like what sort of a follow up what would you think is the.

Speaker Change: Expectations for satellite reduction and then book.

Gary Romano: That's a good question. So you know, since we see this MRI finding that resembles ariop in every in every in every manner. You know, we wouldn't be surprised if we were lowering amyloid. We also wouldn't be surprised given that the fact that this is a our our our our we believe that ails are two will restore microglial function. And we know that microglia are, you know, involved in compacting and also clearing amyloid and other misfolded proteins in, during, under regular conditions and also are involved in removal of amyloid after they get tagged by anti-amyloid antibodies.

Gary Romano: So, you know, since we see this MRI finding that resembles ARIP in every in every in every manner, we wouldn't be surprised if we're lowering amyloid. We also wouldn't be surprised given that the fact that this is a, our, our, our, we believe that AL002 will restore microglial function. We know that microglia are, you know, involved in compacting and also clearing amyloid and other misfolded proteins during, under regular conditions and are also involved in removal of amyloid after they get tagged by anti-amyloid antibodies. So it doesn't surprise us that we would see that.

Speaker Change: Yes, Thats a good question so.

Speaker Change: Since we see this MRI.

Speaker Change: MRI finding that resembles area and every in every in every manner.

Speaker Change: We wouldn't be surprised approval re amyloid, we also wouldn't be surprised given that the fact that this is a R. R.

Speaker Change: We believe that ALC is here to Wil.

Speaker Change: Restore microglia function and we know that microglia are.

Speaker Change: We're involved in.

Speaker Change: And.

Speaker Change: Compacting and also clearing amyloid another misfolded proteins.

Speaker Change: During under regular.

Speaker Change: Conditions and also are involved in removal of amyloid after they get tagged by anti amyloid antibodies. So it doesn't surprise us that we would we would see that in terms of the expectation.

Gary Romano: So it doesn't surprise us that we would see that in terms of the expectation. You know, we we don't know yet and and what we know we haven't we haven't yet looked. But I would tell you that we don't see. I think this is a really important point. We you know, this is this is really a this is a truly different mechanism than anti-amyloid antibodies. And, and it has, as we described in our presentation, you know, we are we are by restoring microglial function. We were storing, you know, many different downstream mechanisms by which microglia preserve brain health.

Gary Romano: In terms of the expectation, you know, We don't know yet, and we haven't, we haven't yet looked, but I would tell you that we don't see this as a really important point. We, you know, this is, this is really a, this is a truly different mechanism than anti-amyloid antibodies. And it has, as we described in our presentation, you know, we are, by restoring mycoglial function, we're restoring, you know, many different downstream mechanisms by which mycoglia preserve brain health.

Speaker Change: We don't know yet.

Speaker Change: We havent, we havent, yet look, but I would tell you that we don't see.

Speaker Change: This is a very important point.

Speaker Change: This is this is really this.

Speaker Change: As a truly different mechanism than anti amyloid antibodies and it has.

Speaker Change: As we described in our presentation.

Speaker Change: We are we are restoring microbial function we're restoring.

Speaker Change: Many different downstream mechanisms by which microglia preserved brand health. So so we don't this is really not intended to be just an amyloid lowering agent and therefore.

Gary Romano: So, so we don't, this is really not intended to be just an amyloid lowering agent. Therefore, if we do or do not reach the if the one amyloid, you know, the 24 centroid level that seems to be necessary condition for clinical efficacy for the anti-amyloid antibodies, that's not going to bother us. And we're not going to make a decision based on that because, you know, this really goes beyond amyloid. clearance, just mechanism. Thank you so much. I really appreciate that. Yep.

Gary Romano: So, we don't, this is really not intended to be just an amyloid lowering agent. Therefore, if we do or do not reach the 24 centeloid level that seems to be a necessary condition for clinical efficacy for the anti-amyloid antibodies, that's not going to bother us. And we're not going to make a decision based on that because, you know, this really goes beyond amyloid. Thank you so much.

Speaker Change: If we do or do not reach the.

Speaker Change: The amyloid 24, <unk> level that seems to be necessary condition for clinical efficacy for the anti amyloid antibodies, but thats not going to bother us and we're not going to make a decision based on that because this really goes beyond amyloid clearance. This mechanism.

Michael Riad: Thank you so much. I really appreciate that.

Speaker Change: Thanks, so much I appreciate that.

Samantha: One moment for our next question. And our next question comes from Pete Stavropoulos with Cantor Fitzgerald. Hi, this is Samantha on the line for Pete. Thanks for taking our questions.

Samantha: One moment for our next question. Our next question comes from Pete Stavropoulos with Cantor Fitzgerald.

Speaker Change: One moment for our next question.

Speaker Change: And our next question comes from Pete Stavropoulos with Cantor Fitzgerald.

Samantha: Hi, this is Samantha on the line for Pete. Thanks for taking our questions. Firstly, for TREM 2, can you give us an idea of what to expect for the first data release next quarter? And what's the bar for moving this program forward into a later stage study? Will it be biomarker driven, or do you need to see a clear signal of clinical efficacy? And regarding safety monitoring, is it safe to assume that ARIA-like observations have been minimized due to the protocol changes?

Samantha: Hi, This is Samantha on the line for Pete Thanks for taking our questions. Firstly for trim to can you give us an idea of what to expect for the first data release next quarter, what's the bar for moving this program forward into a later stage study will be biomarker, driven or do you need to see a clear signal of clinical efficacy.

Samantha: Firstly, for Trem too, can you give us an idea of what to expect for the first data release next quarter? What's the bar for moving this program forward into a later stage study? Will it be biomarker driven, or do you need to see a clear signal of clinical efficacy? And regarding safety monitoring, is it safe to assume that aria-like observations have been minimized due to the protocol changes? Has there been any new KOL feedback on what might be driving these observations?

Speaker Change: And regarding safety monitoring is it safe to assume that Oreo like observations have been minimized due to the protocol changes has there been any new kols feedback on what might be driving these observations and finally regarding the ADC technology could you describe the tissues are cell types, where Cte 98.

Samantha: Has there been any new KOL feedback on what might be driving these observations? And finally, regarding the ABC technology, could you describe the tissues or cell types where CD98 is expressed and outline any theoretical risks associated with targeting CD98? Thanks so much.

Samantha: And finally, regarding the ABC technology, could you describe the tissues or cell types where CD-98 is expressed and outline any theoretical risks associated with targeting CD-98? Thanks so much. Okay, thanks. Good questions. Thanks, Samantha. So what to expect for in terms what do you expect in terms of what data we're going to report? We're going to we'll have a press release and that press release will include not only the typical top line primary clinical outcomes and safety, but we're also going to include data on the relevant biomarkers. As I said, at distance, we were making a decision based on a combination of clinical, functional, and biomarker readouts, and we have lots of biomarkers.

Speaker Change: As expressed an outline any theoretical risks associated with targeting CD 98, thanks, so much.

Gary Romano: Okay, thanks. Good questions. Thanks, Samantha.

Samantha: Okay. Thanks, good questions. Thanks Samantha.

Speaker Change: So what to expect.

Samantha: Yes.

Speaker Change: What you expect in terms of what data we're going to report we're going to it will have a press release in that press release will include not only.

Gary Romano: So, what do you expect in terms of the data we're going to report? We'll have a press release, and that press release will include not only the typical top-line primary clinical outcomes and safety, but we're also going to include data on the relevant biomarkers. As I said, we're making a decision based on a combination of clinical, functional, and biomarker readouts, and we have lots of biomarkers. So, all of those that are relevant to making a decision, particularly the Alzheimer's physiology biomarkers, will be included. And what is the bar to advance?

Samantha: The typical topline primary clinical outcomes and.

Samantha: And safety, but were also going to include data on the relevant Biomarkers. If I said this is where we're making a decision based on a combination of clinical functional and biomarker readouts. We have lots of biomarkers. So all of those all of those that are relevant to making a decision.

Gary Romano: So all of those that are relevant to making a decision, you know, particularly the Alzheimer's physiology biomarkers, will be included, will be reporting out on. We intend to report out on all of those at the same, you know, with the press release, not just top line. And what is the bar to advance? I just said it, right? It's it's some combination there of and seeing consistency across those those clinical and biomarker outcomes that showing that we are slowing disease progression because that's that in the end of the day, that's that's what we're up to do.

Samantha: Particularly the Alzheimer's disease Biomarkers will be included will be reporting add on.

Samantha: We intend to report out on all of those at the same with the press release not just topline.

Gary Romano: I just said it, right, it's some combination there of, and seeing consistency across those clinical and biomarker outcomes that show that we are slowing disease progression because, at the end of the day, that's what we're out to do. So it's not going to be, you know, it's not going to be about hitting a p-value or just a clinical outcome measure that, you know, that's, if we do or don't, if we see directional effects there consistent with biomarkers showing slowing of disease progression, for us, that's a win, and we'll be very excited to see that and advance the compound.

Speaker Change: And what is the bar to advance.

Samantha: Just said it right.

Samantha: Some combination there.

Samantha: And see consistency across those clinical and biomarker outcomes.

Samantha: That's showing that we are slowing disease progression because thats.

Samantha: And the end of the day.

Samantha: That's what we're out to do.

Gary Romano: So it's not going to be, you know, it's not going to be about hitting a p-value or on just clinical outcome measure that, you know, that's if we do or don't, if we see directional effects there consistent with biomarker, but, you know, directional effects showing slowing of disease progression for us, that's a win and that that's that's that's it would be very excited to see that and advance the compound. You also asked about area; is it do we think it's minimized? Well, what we do know is that when we, after we drop the APOE4s, we then added MRI surveillance, and MRI surveillance actually, we were doing it every four weeks before each dose of titration for the first three months and then less often after that.

Samantha: So it's not going to be it's not going to be about hitting a P value or.

Samantha: And then just clinical outcome measure that.

Samantha: If we do or don't if we see directional effects there consistent with biomarker.

Samantha: Directional effects showing slowing of disease progression for us that's a win in.

Samantha: We'll be very excited to see that in advance the compounds.

Gary Romano: You also asked about area, is it, do we think it's minimized? Well, what we do know is that when we, after we dropped the APOE-4s, we then added MRI surveillance. And MRI surveillance, actually, we were doing it every four weeks before each dose of titration for the first three months, and then Unknown Speaker Less often after that. We know that likely increases the amount of ARIA you're going to find because you're looking every four weeks for radiographic ARIA, which is 90 percent of the ARIA.

Samantha: You also asked about area is it do we think it's minimized well what we do know is that when we when we.

Samantha: After we dropped the April before as we then added MRI surveillance and MRI surveillance actually.

Samantha: We were doing it every every four weeks before each dose titration for the first three months and then.

Samantha: Less less often after that.

Gary Romano: We know for, you know, that that that likely increases the amount of area you're going to find because you're looking very every four weeks for radiographic area, which is 90% of the area, really by the way reported at that in their, the NMAP phase three program that they, when they added area surveillance, increased the area surveillance, they saw more. Also, they saw in addition to seeing it more, higher incidence, they also found that the severity was reduced. And we've also observed that, you know, as I said, the incidence and severity of area has, you know, has actually come down for us in our study, you know, under the current population. You know, is it minimized meaning is that as low as it can go?

Samantha: No.

Speaker Change: That that likely increases the amount of area youre going to find because youre looking every four weeks.

Samantha: For radiographic area, which is 90% of the area.

Gary Romano: Lilly, by the way, reported that in their BANANAMAP Phase 3 program that when they increased the ARIA surveillance, they saw more ARIA; also, in addition to seeing it more often, they also found that the severity was reduced. And we've also observed that, you know, as I said, the incidents and severity of the area have, you know, actually come down for us in our study, you know, under the current population. Is it minimized? Meaning is that as low as it can go?

Dave: Really by the way reported that in their <unk> phase III program that Dave and I added area of surveillance increased CRE surveillance. They saw Marty how are you.

Speaker Change: Also they saw in additionally.

Marty: More higher incidents.

Marty: They also found that the severity was reduced and we've also observed that as I said the.

Marty: Incidents and severity of area has.

Marty: <unk>.

Marty: Actually come down for us in our study.

Marty: The current population.

Samantha: Is it minimized, meaning is that as low as it can go.

Gary Romano: I don't know; we don't, you know, we don't know that for sure, but I can tell you that in our long-term extension, one of the things that we're exploring is whether starting at a lower dose and titrating more slowly, akin to what they've been doing in the anti-analysis antibody trials, could reduce the area's signal. So we hope to learn that as well in our, as in our long term extension study.

Gary Romano: I don't know. We don't, you know; we don't know that for sure. But I can tell you that in our long-term extension, one of the things that we're exploring is whether starting at a lower dose and titrating more slowly, akin to what they've been doing in the amyloid anti-amyloid antibody trials, could reduce the area signal, so we hope to learn that as well in our long-term extension.

Speaker Change: I don't know, we don't we don't know that for sure, but I can tell you that.

Speaker Change: Long term extension one of the things that we're exploring is weather sorry.

Speaker Change: Starting at a lower dose and and tight trading more slowly akin to what they've been doing in the <unk>.

Marty: Anti <unk> antibody trials.

Speaker Change: Could we do see the RF signals, so that we hope to learn that as well.

Marty: And our long term extension study.

Sara Kenkare: And what is the mechanism? Yeah, it was the mechanism. I'm sorry, but I think the last session was talking about what, what about mechanism? Everyone we, we, we show this to says this has to be related to amyloid clearance. We're very, I'm kind of conservative, so I'll wait till I see the data, but I think that's a good bet.

Marty: And.

Gary Romano: Oh, what does the mechanism do? Yeah, it was the mechanism. I'm sorry. Well, I think the last session was talking about the mechanism. Everyone we show this to says this has to be related to amyloid clearance. We're very, I'm kind of conservative. So I'll wait till I see the data. But I think that's a good bet. And I think there's a CD98 question for Sara.

Speaker Change: What's the third question is the mechanism.

Speaker Change: The mechanism I'm, sorry, but I think the last question was something about what about the mechanism.

Speaker Change: Everyone's we show. This two says this has to be related to amyloid clearance.

Speaker Change: We're very.

Speaker Change: I am kind of conservative so I'll wait till I see the data, but I think thats, a good bet and I think theres a seeding idea question for Sarah.

Sara Kenkare: And I think there's a CD 98 question for Sara. Yeah, yeah, according to the, to the human protein atlas, sort of CD 98 is expressed in endocrine tissues in the pancreas, in the kidney, in genitalia, and a little bit in the skin. So yeah, we will be looking if there's any adverse effects in these tissues in the brain. CD 98 is expressed higher.

Sara Kenkare: Yes. Yes. Yes. Yes.

Sarah: Yes, yes, yes.

Speaker Change: According to the.

Sara Kenkare: According to the human protein atlas, CD98 is expressed in endocrine tissues, in the pancreas, in the kidney, in genitalia, and a little bit in the skin. So yeah, we will be looking if there are any adverse effects in these tissues. In the brain, CD98 is expressed higher in supporters in microglia and astrocytes and at lower levels in neurons outside of the endothelial cells, which enable the use of it as a blood and barrier.

Speaker Change: Yes.

Speaker Change: So the human protein plus total Stephen Lang, <unk>, president and the credit issues.

Speaker Change: In the pancreatic the keathley in Germany and Italy.

Speaker Change: Between the scheme. So yes, we will be looking at.

Speaker Change: Perfect.

Speaker Change: Sure.

Speaker Change: Keep in mind the IP.

Speaker Change: Express.

Sara Kenkare: In supporters in microglia and atrocyte and lower levels in neurons outside of the endothelial cells, which enable the using it as a blood barrier. Thanks.

Speaker Change: Sure.

Speaker Change: In football.

Speaker Change: Microglia and Thats too.

Speaker Change: Lower local neuro outside of the endothelial cells, which enabled.

Speaker Change: Using it because it doesn't failure.

Speaker Change: Sure.

Sara Kenkare: So, thank you so much.

Samantha: This is so helpful. Thank you so much.

Nick: Thanks, Nick thank.

Nick: Thank you so much.

Brandon: One moment for our next question. The next question comes from Yaron Verber with PD Cowan. Hi, this is Brandon on for your own.

Nick: Yeah.

Operator: One moment for our next question. Our next question comes from Yaron Verber with TD Cowan. Hi, this is Brendan on for your own. Thanks for taking the questions, guys.

Speaker Change: One moment for our next question.

Speaker Change: Your next question comes from <unk> <unk> with TD Cowen.

Brendon: Hi, This is brendon on for your own thanks for taking the questions guys.

Brandon: I think we're taking the questions, guys. Actually, just a quick one on the potential at the often payment. Can you maybe just remind us when what the timing is to potentially book that if the data comes out Q4 and was good, do you expect them, would you expect the book that after the phase two data may be in Q1 or are there other dating factors there. And just kind of let us know how you would report that. And then obviously just looking at the deep effect I was just wondering which of the target programs you may expect into the clinic first when you think that might happen.

Brendon: Actually just a quick one on the potential abbvie opt in payment can you maybe just remind us.

Speaker Change: When what the timing into potentially books that if the data comes out Q4 and look good do you expect would you expect to book that after the phase II data maybe in Q1 are there other gating factors, there and just kind of let US know how you would report that and then obviously just looking at the deeper part I was just wondering which of the target programs you may expect to enter the clinic first.

Speaker Change: When do you think that might happen.

Gary Romano: Thanks. Yeah, thanks for the questions, Brennan. So, as it relates to the option payment, would that be as your call that's at their option $250 million at the end of the phase two. So we're aligned with them around the concept study package. And we plan to be sharing that package with them at the end of this year, Q4 of this year. And if they have 90 days, close very shopping for that pack. to decide if they're opting in so that that would put the payment, you know, towards the end of 21 early Q2 is our expectation currently.

Brendan: Yeah, thanks for the questions, Brendan. As it relates to the option payment with AbbVie, as you recall, that's at their option $250 million at the end of phase two. So we're aligned with them around the concept study package, and we plan to be sharing that package with them at the end of this year, Q4 of this year. And if they have 90 days post, they're accepting for that package to.

Speaker Change: Yes. Thanks.

Speaker Change: Thanks for the questions Brandon so as it relates to the option payment with Abbvie.

Speaker Change: You recall.

Speaker Change: At their option $250 million at the at the end of the phase III. So we're aligned with them around the proof of concept study package and we plan to be sharing that package with them.

Speaker Change: At the at the end of this year Q4 of this year.

Speaker Change: They have 90 days post their acceptance of that package.

Unknown Executive: I'd decide if they're opting in, so that would put the payment, you know, towards the end of Q1, early Q2, which is our expectation currently. And then, you know, your second question around which of the programs in our earlier portfolio will be advancing and, you know, which is the most advanced? We have a number of disclosed programs and a number of undisclosed programs, and, you know, we look forward to providing you updates around that portfolio as the coming year progresses. We haven't specifically made a statement at this time as to which one is advancing.

Speaker Change: Yes.

Speaker Change: Decide if theyre opting in so that would put the payment.

Speaker Change: Towards the end of Q1.

Speaker Change: Early in Q2 as our expectation currently.

Gary Romano: And then, you know, your second question around, you know, which of the programs in our earlier portfolio will be advancing, and, you know, which is the most advanced. We have a number of disclosed programs and a number of undisclosed programs and.

Speaker Change: And then.

Speaker Change: Your second question around.

Speaker Change: Which are the programs at our <unk>.

Speaker Change: Earlier portfolio will be advancing and then.

Speaker Change: Yes.

Speaker Change: The most advanced we have a number of disclosed programs in a number of undisclosed programs.

Gary Romano: You know, we look forward to providing you updates around that portfolio as next year progresses in the coming years. We haven't specifically made a statement at this time as to which one is advancing first. I'll play that. I'm spread it. Yeah, great.

Speaker Change: We look forward to providing you updates.

Speaker Change: That portfolio is.

Speaker Change: Next year progresses.

Speaker Change: In the coming years, we havent specifically.

Speaker Change: I made a statement at this time as to as to which one is advancing first.

Brandon: Hopefully that helps Brandon.

Brandon: Thanks, guys.

Brandon: Yeah, that's great. Thanks, guys.

Carter Gould: One moment for our next question. The next question comes from Carter Gould with Barclays. Good afternoon. Thanks for taking the question. I guess first off, I want to be clear on exactly what's sort of being message coming out of that type of meeting. It's appreciating your affirmation of confidence in the primary end point, but it sounds like this is the contingency strategy in the context of a potentially critical data on the primary. Is that a fair characterization in any way represent an evolution of your regulatory strategy on that program. And then I guess just to follow up on coming out of invoked to it sounds like there'll be a separation of data and path forward.

Operator: One moment for our next question, and our next question comes from Carter Gould with Barclays.

Speaker Change: One moment for our next question.

Speaker Change: And our next question comes from Carter Gould with Barclays.

Carter Gould: Good afternoon. Thanks for taking the time to answer the question. I guess first off, I want to be clear on exactly what's sort of being messaged coming out of that Type B meeting. It appreciates your affirmation of confidence in the primary endpoint, but it sounds like this is a contingency strategy in the context of potentially equivocal data on the primary. Is that a fair characterization, and does this in any way represent an evolution of your regulatory strategy for that program?

Carter Gould: Hi, good afternoon. Thanks for taking the question I guess first off I wanted to be clear on exactly what sort of being message coming out of a type b meeting.

Carter Gould: I appreciate it.

Speaker Change: Affirmation of confidence in the primary endpoint, but it sounds like this is the conclusion to strategy in the context of potentially clinical data on the primary is that is that a fair characterization or is this in any way represents an evolution of your regulatory strategy.

Carter Gould: And then I guess just to follow up on coming out of Invoke 2, it sounds like there'll be a separation of data and path forward. So I guess, I guess, again, is that sort of a fair characterization that we shouldn't expect any sort of commitment on moving the product forward necessarily when we get the data? And I guess alongside that, as we think about AbbVie and their decision process, they did recently de-prioritize or discontinue their A beta program. How do you do that? And if there's any, read through to 002. Thank you.

Speaker Change: On that program and then I guess just to us.

Speaker Change: Follow up on on coming guys coming out of invoke too.

Speaker Change: It sounds like there'll be a separation of data and path forward. So I guess again is that sort of a fair characterization that we shouldnt expect any sort of.

Carter Gould: So I guess, again, is that sort of a fair characterization that we shouldn't expect any sort of commitment on moving the products forward necessarily? Wouldn't we get the data. And I guess alongside that, as we think about Abby and their decision process, they did recently be prioritized or discontinued their a beta program. How do you do that? And if there's any read-through to. As yours are too. Thank you. Thanks for the question, Kar.

Speaker Change: Commitment on moving the products forward necessarily when we get the data.

Speaker Change: I guess alongside that as we think about abbvie in their decision process. They did recently de prioritize or discontinue their a beta program. How do you view that and if theres any read through too.

Carter Gould: Thanks for the questions, Carter. Maybe, Gary, you can take the first question and I'll take the latter two. Yeah, yeah, sure.

Speaker Change: Thank you.

Gary Romano: Maybe, Gary, you can take the first question. I'll think the latter two. Yeah, yeah, sure. So that's so clear. Thanks for your question. No, this really is not a contingency strategy. We are committed and we're optimistic that, you know, we can we can get a full approval based on the primary outcomes, secondary outcomes, and the biomarkers. Our questions were really, you know, can we, are these the biomarkers? There's a lot of biomarkers one could look at. We felt that the ones that we proposed were biomarkers that, if we were to see effects, these are biomarkers that are prognostic to begin with.

Speaker Change: Thanks for the question Scott, maybe Gary you can take the first question I'll take the latter two.

Gary Romano: Yeah, yeah, sure. So, Carter, thanks for your question. No, it's really not a contingency strategy.

Gary: Yeah sure so thanks.

Speaker Change: Thanks for your question.

Speaker Change: No. It's really it's not a contingency strategy. We are we are committed and we are at.

Gary Romano: We are, we are committed, and we're optimistic that, you know, we can get a full approval based on the primary outcomes, secondary outcomes, and the biomarkers. Our questions were really, you know, can we do these about, you know, are these the biomarkers? There are a lot of biomarkers one could look at, but we felt that the ones that we proposed were biomarkers that, if we were to see effects, these would be biomarkers that are prognostic to begin with.

Gary: Optimistic that we can we can get a full approval based on the primary outcome secondary outcomes in the Biomarkers are questions. We're really.

Speaker Change: Can we or the use of <unk>.

Speaker Change: Are these the biomarkers.

Speaker Change: There's a lot of Biomarkers one could look at we felt that the ones that we proposed.

Speaker Change: Biomarkers that if we were to see effects.

Speaker Change: Our biomarkers that are prognostic to begin with so if you see changes with NFL or.

Gary Romano: So, you know, if you see changes in NFL or GFAP even before there are symptoms, you see changes in volumetric MRI even before symptoms. So it's, it's, it's a prognostic biomarker. We don't know yet whether it is a surrogate marker, but but, you know, but we would imagine that, you know, because you see these changes even in advance of clinical symptoms, that changes in the trajectories of these biomarkers should support the clinical outcome. This is a single study. It's a relic, you know; it's a rare disease. So it's a relatively small study. It's 100 patients.

Gary Romano: So, you know, if you see changes in NFL or GFAP, even before there are symptoms. You see changes in volumetric and arrived even before symptoms. So it's a prognostic biomarker. If we don't know yet whether it is a surrogate marker, but you know, but we would imagine that, you know, because you see these changes, even in advance of clinical symptoms, that changes in the trajectories of these biomarkers should support. The clinical outcome. This is a single study. It's a relic, you know; it's a rare disease. So it's a relic as a relatively small study. It's 100 patients and.

Speaker Change: Even before there are symptoms.

Speaker Change: Do you see changes in volumetric MRI, even before symptoms. So it's a prognostic biomarker.

Speaker Change: If we don't know yet whether it is a surrogate marker, but but but we would imagine that because you see these changes even in advance of.

Speaker Change: Clinical symptoms that changes in the trajectory of these biomarkers should support.

Speaker Change: The clinical outcome. This is a single study it's a relative.

Speaker Change: Rare disease, so it's a.

Gary Romano: And and so, you know, we're always thinking and looking about how, you know, how to devise our statistical analysis plan in a way that that that, you know, can best show that the drug is providing benefit. And we thought these were important questions to ask. You know, if they didn't think these biomarkers were relevant or good enough or whatever, then then, you know, we would have to maybe think differently about our SAP. But we were very encouraged by this information. We really are committed to, you know, for a full approval.

Speaker Change: <unk> small study, it's 100 patients and.

Gary Romano: And so, you know, we're always thinking and looking about how, you know, how to devise our statistical analysis plan in a way that, that, you know, can can best show that the drug is providing benefit. And we thought these were important questions to ask. You know, if they didn't think these biomarkers were relevant or good enough or whatever, then, you know, we would have to think differently about our RSA P. But we were very encouraged by this information. We really are committed to, you know, for a. and a full approval based on the totality of the data.

Speaker Change: And so we're always thinking looking about.

Speaker Change: Device, our statistical analysis plan in a way that that that can.

Speaker Change: Can best show that the drug is providing benefit and we thought these are important questions to ask.

Speaker Change: They didn't think these biomarkers where relevant or good enough for whatever then we would have maybe think differently about our our SAP, but we are very encouraged by the information we really are committed to it.

Speaker Change: <unk>.

Speaker Change: A full approval based on on the <unk>.

Speaker Change: Fatalities with data.

Gary Romano: Yeah, and I think your second question, Carter, related. So, we were answering the question. The prior analyst was asking about the, I think, the earlier pipeline in which programs would advance next, not referring to. Trim, too, you know, that, that program, obviously, you know, subject to at least opt-in decision, that would be a component. But, you know, we're looking forward to advancing that. We expect the next stage would be a phase three. If they opt in, if they would be taking on that phase three, and we share 50, 50 in the cost and also the profits, is that program advances in remind me your third question, Carter.

Unknown Executive: Yeah, and I think your second question Carter related, so we were answering the question a prior analyst was asking about the I think the earlier pipeline in which programs would advance next, not referring to Trim 2, you know, that program, obviously, you know, subject to AVI's opt-in decision, that would be a component. But, you know, we're looking forward to advancing that. We expect the next stage to be a Phase 3. If they opt-in, they will be taking on that phase 3, and we will share 50-50 in the costs and also the profits as well. And remember, your third question, Carter?

Carter Gould: Yes, and I think your second question Carter related.

Speaker Change: We were answering the question.

Speaker Change: Prior.

Speaker Change: And also it was asking about I think the earlier pipeline and which program would it be.

Speaker Change: Thats snacks, not not referring to.

Speaker Change: Turning to <unk>.

Speaker Change: S program, obviously subject to.

Abbvie: Abbvie is.

Speaker Change: Tim decision that would be a component.

Speaker Change: We're looking forward to advancing that we expect the next stage would be a phase III if they opt in they would be taking on.

Speaker Change: That phase III and we share.

Speaker Change: 50 50.

Speaker Change: And the.

Speaker Change: And the cost and also the profit is that program.

Speaker Change: Advances and remind me your third question Carter.

Unknown Executive: Again, any read-through from AVI's decision to de-prioritize and discontinue their A-Beta program? On some level, you could say that's narrowing their their their Alzheimer's portfolio, and if you see any read through them to around their interest in 002. Yeah, yeah, it's really hard for us.

Gary Romano: Again, any read through from Abby's decision to deprioritize and just continue their a beta program sort of on some level, you could say that it's narrowing their, their, their all time was portfolio and you see any read through them to around their interest in zero zero to thank you. Yeah, yeah, it's really hard for us to speculate there. Maybe they didn't see the differentiation they were looking for with that beta program relative to what else is out there. Again, you know, we've remind you know that the broader mechanism and, you know, the complimentary role at activation of microglia can play.

Speaker Change: Again any read through from <unk> decision to de prioritize or just continue there a beta program sort of.

Speaker Change: Im level, you could say that's narrowing there.

Speaker Change: Theyre all diverse portfolio and if you see any read through them around their interest in <unk>. Thank you.

Unknown Executive: Yeah, yeah, it's really hard for us to speculate there. Maybe they didn't see the differentiation they were looking for with that A-beta program relative to what else is out there.

Speaker Change: Yes, it's really hard for us to speculate there.

Speaker Change: Maybe they didn't see the differentiation that they were looking for.

Speaker Change: With that a beta program relative to what else is out there again, we would remind.

Unknown Executive: Again, you know, we remind ourselves of the broader mechanism and the complementary role that activation of microglia can play. So we don't necessarily see a read-through there, but that's our speculation. What we can say is we're very aligned with A-b, including around, as I mentioned, the You know, as Gary's highlighted, you know, the phase two data readout and the concept study package that's associated

Speaker Change: The broader mechanism.

Speaker Change: The complementary role that activation of microglia I can't play.

Gary Romano: So we don't, we don't necessarily see a read through there, but, you know, that's, that's, you know, our speculation. What we can say is, you know, we're very aligned with, would that be, including around, as I mentioned, the, you know, scary highlighted. The phase two data readout of the concept study package that's associated with that. Thank you.

Speaker Change: Play so we don't.

Speaker Change: We don't necessarily see.

Speaker Change: Read through there, but that's our speculation, but we can say is we're very aligned with with abbvie, including around as I mentioned.

Speaker Change: And.

Gary: As Gary highlighted.

Gary: The phase II data readout in proof of concept study package thats associated with that.

Speaker Change: Thank you.

Tom Schrader: One moment for our next question. The next question comes from Tom Schrader with BTIG. A good afternoon. Thanks for taking the question. They're on Progress AD, the trial with 101. Have you seen it or are you going to update us if you're going to see if you've seen the MRI signal characteristic of Arya? It's obviously interesting here, but at some level it doesn't it be risk the entire program you'll in program if you did see some Arya?

Operator: One moment for our next question, and our next question comes from Tom Schrader with BTIG.

Speaker Change: One moment for our next question.

Speaker Change: And our next question comes from Tom Shrader with <unk>.

Tom Schrader: Good afternoon. Thanks for taking the question. They're in PROGRESS-AD, the trial with 101. Have you seen or are you going to update us on whether you've seen the MRI signal characteristic of ARIA? It's obviously interesting here, but at some level, doesn't it de-risk the entire progranulin program if you did see some?

Tom Shrader: Hi, good afternoon, thanks for taking the question there on progress.

Tom Shrader: While with 101 have you seen it where are you going to update us if youre going to see if you've seen the MRI signal characteristic of ARIA.

Speaker Change: It's obviously interesting here, but at some level it doesn't it derisk the entire pro granular program. If you did see some ARIA.

Tom Schrader: Yeah, that's a good question, Tom. As always, you know, we, we have, we don't have any recent, well, we, we, we because this mechanism of action involves, we think involves microglia at, you know, we have built into the study. MRI surveillance to look and see if we, if we have area. I can tell you that, you know, we haven't seen, you know, we haven't seen any such signals thus far. Study it's early days with that study. Would it be risk the program? You mean in the sense that it would somehow, you know, or cellular sort of and does some does what it's supposed to?

Gary Romano: Yeah, that's a good question, Tom, as always, we don't have any reason, well, we, because this mechanism of action involves, we think involves microglia, and, you know, we have built into the study MRI surveillance to look and see if we, if we have an area. I can tell you that, you know, we haven't seen any such signals thus far in this study. It's early days with that study.

Speaker Change: Yes, that's a good that's a good question time as always.

Speaker Change: We have.

Speaker Change: We don't have any risk as well.

Speaker Change: We because this mechanism of action.

Speaker Change: <unk>.

Speaker Change: We think involves microglia.

Speaker Change: We have built into the study.

Speaker Change: MRI surveillance to to look and see if we if we have area.

Speaker Change: I can tell you that.

Speaker Change: We have we haven't seen we haven't seen any such signals. Thus far study it's early days with that study.

Gary Romano: Would it de-risk the program? You mean in the sense that it would somehow, you know, I, yeah, yeah, I suppose so. I mean, I think, I think, yeah, I mean, I think in the same way that we think about it in AL002, it would be, it would be, in some ways, encouraging about biological activity. But, but, you know, so far, we just, you know, we're looking, we're mostly just making sure we don't miss a safety signal that we need to keep an eye on. But We haven't seen anything else yet.

Speaker Change: When it Derisked the program you mean in the sense that it would.

Speaker Change: Somehow cellular.

Speaker Change: Cellular sort of Windows does what its supposed yeah.

Gary Romano: Yeah, yeah, I suppose so. I mean, I think, I think, yeah, I mean, I think in the same way that we think about it in Al-002 would be, it would be in some ways encouraging about biological activity, but, you know, so far we just, you know, we're looking, we're looking mostly, you know, we could just make sure we don't miss a safety signal that we need to keep an eye on. But we haven't seen anything else. Yeah.

Speaker Change: I suppose so I mean, I think I think yes.

Speaker Change: I think in the same way that we think about it in <unk> year on year or two would be it would be in some ways encouraging about biological activity.

Speaker Change: <unk>.

Speaker Change: But so far we just.

Speaker Change: Were looking mostly.

Speaker Change: To make sure we don't Miss a safety signal that we need to keep an eye on.

Speaker Change: But we haven't seen anything as yet.

Tom Schrader: And real quick, is increasing progranulin to high levels, based on the biology that you guys are so into, is that as broad an effect as increasing TREM-2? It almost seems like a step backwards, that you're fixing the lysosome and hoping everything else follows. Rather, TREM-2 forces everything. Is that a fair characterization?

Gary Romano: And real quick, it is increasing pro-granulant to high levels based on the biology that you guys are so into, is that as broad an effect as increasing trim too. It almost seems like a step backwards that you're fixing the lice is home and hoping everything else follows rather trim too forces everything. Is that a fair characterization?

Speaker Change: And real quick.

Speaker Change: <unk> is increasing pro granular into high levels based on the biology that you guys are still went through is that as broad an effect is increasing trim to it almost seems like a step backwards that you're fixing the lysosomal, hoping everything else follows rather trim two forces everything is that a fair.

Speaker Change: Characterization.

Unknown Executive: Arnon, I'm happy to answer that or if you want to speak to it.

Gary Romano: Arnon, do you want to? I'm happy to answer that. Or do you, of course, want to speak to it? Yeah, it is a different mechanism, but pro-granuling also has a very broad range of activities. It is a lice, as I'm on shaperone, as you said, it enhances some of the activity which is a critical component in fighting misfolded protein, but it's also a survival factor for multiple types of neuron. It sort of enhances, no sort of normal activity. So we think that these are different mechanisms, and we think that because now the generation is such sort of such a large and met me, it's worth testing multiple mechanisms. We don't think that pro-granuling is less broad or is sort of similar to anti-beta antibodies, for example.

Speaker Change: Do you want Im happy to answer that.

Speaker Change: You want to speak to it.

Arnon Rosenthal: Yeah, it is a different mechanism, but programming also has a very broad range of activities. It is a lysosomal chaperone, as you said, it enhances lysosomal activity, which is a critical component in fighting misfolded proteins, but it's also a survival factor for multiple types of neurons. It sort of enhances, not exactly neuronal activity. So we think that these are different mechanisms, and we think that Because now the generation is such a large unmet need, it's worth testing multiple mechanisms. We don't think that programming is less broad or is sort of, It's similar to anti-abeta antibodies, for example. We think that progranolone is sufficiently broad to address multiple disease pathologies.

Speaker Change: Yes. It is.

Speaker Change: As a different mechanism, but <unk> also has a very broad range of activities.

Speaker Change: Likewise, our chaperone.

Speaker Change: From an activity, which is the key.

Speaker Change: We've been kind of component in fighting we folded protein, but it's also it's an environmental factor for multiple types of neurons.

Speaker Change: So.

Speaker Change: No no.

Speaker Change: Activity.

Speaker Change: We think that these are different mechanisms and we think that.

Speaker Change: Okay.

Speaker Change: Because no other generics.

Speaker Change: Such a lot of unmet need.

Speaker Change: <unk> multiple.

Speaker Change: <unk>.

Speaker Change: But we don't think that.

Speaker Change: This brought the total.

Speaker Change: We are seeming to want a beta antibody for example, rethink that.

Unknown Executive: We think that pro-granuling is sufficiently broad to address multiple disease pathologies. Okay, great. Thanks for the details. One moment for our next question.

Speaker Change: So presuming sufficiently broad to address multiple pathologies.

Tom Schrader: Okay, great. Thanks for the details.

Speaker Change: Okay, great. Thanks for the <unk>.

Speaker Change: Details.

Operator: One moment for our next question. The next question comes from Myles Minter with William Blair and Company.

Speaker Change: One moment for our next question.

Unknown Executive: Our next question comes from Miles Minter with William Blair in Company.

Speaker Change: Our next question comes from Myles Minter with William Blair <unk> Company.

Unknown Executive: Hi, yeah, you've got Sarah on for miles. Congrats on the progress and things for taking our questions. So if you just remind us whether all those successes in Invoke Two would potentially be therapeutic. And as it relates to your powering assumptions, are you expecting to pool those treated patients or consider each dose are individually. And second, now that we've seen the baseline characteristics in your view, how do these patients compare to those enrolled in other 80 therapeutic trials we've seen regarding various age of disease and biomarkers, and do you think the entire range of joking, including 48 weeks.

Sara: Hi, yeah, you've got Sara on for Myles. Congratulations on the progress, and thanks for taking our questions. So, can you just remind us whether all doses tested in Invogue 2 would potentially be therapeutic? And as it relates to your powering assumptions, are you expecting to pool those treated patients or consider each dose arm individually? And second, now that we've seen the baseline characteristics, in your view, how do these patients compare to those enrolled in other AD therapeutic trials we've seen regarding severity, stage of disease, and biomarkers? And do you think the entire range of dosing, including 48 weeks, will be long enough to see a measurable function decline in the placebo group to potentially separate those treated patients?

Speaker Change: Hi, Sarah on for miles congrats on the progress and thanks for taking our question. So can you just remind us whether all that with the.

Speaker Change: And then <unk> would potentially be therapeutic and as it relates to your powering assumptions are you expecting to pool, those treated patients or consider each dose arm individually and second now that we've seen the baseline characteristics in your view how do these patients compared to those enrolled in other therapeutic trials. We've seen are regarding theory stages with these <unk>.

Speaker Change: And do you think the entire range of dosing, including 48 weeks will be long enough to see a measurable function decline in the placebo group to potentially that break those treated patient.

Gary Romano: It will be long enough to see a measurable function to find enough placebo group to potentially separate from those treated patients. Oh, there are good questions. Thank you. So do we think all doses are therapeutic? Well, yes, because in our phase one study, we saw target engagement. So reductions in soluble trim to the highest in the top two doses, where we saw greater to 50% that they were still robust in the in the low dose that we're testing. And even even lower than that. So you're based on that. I think that that is; it would be therapeutic.

Gary Romano: Okay, questions. Thank you.

Speaker Change: Great question. So thank you. So do we think all doses or therapeutic well, yes, because in our phase one study we saw we saw.

Gary Romano: So do we think all doses are therapeutic? Well, yes, because in our phase one study, we saw target engagement showing reductions in soluble TREM2. They were highest in the top two doses, where we saw greater than 50%, but they were still robust at the low dose that we're testing and even lower than that. So based on that, I think that that would be therapeutic. We also saw increased microGL signaling across multiple pathways, IL-1RN, I think we mentioned this in the call, and CSF1R and SVP1 at all those doses.

Speaker Change: Target engagement.

Speaker Change: Reductions in sight, we will try to they were highest in the top two doses, where we saw greater than 50% that they were still robust.

Speaker Change: And the low dose that we're testing and even be even lower than that.

Speaker Change: So based on that I think that that is.

Gary Romano: We also saw increased increased microglue signaling across multiple pathways, IL1RN. I think we mentioned this in the call and CSF1R and SVP1 at all those doses. So, yeah, we do think that those are potentially therapeutic in terms of the analysis. So we will look at each dose versus placebo, but we will also be pulling data. And in fact, the top two doses are. are overlapping considerably in their PK, and so that's definitely part of our pre-specified analysis that we'll be looking at. Definitely.

Speaker Change: It would be therapeutic we also saw increased that we saw.

Speaker Change: Increased microbial signaling across multiple pathways.

Gary Romano: So yeah, we do think that these are potentially therapeutic. In terms of the analysis, we will look at each dose versus placebo, but we will also be pooling data. And in fact, the top two doses are overlapping considerably in their PK. And so that's definitely part of our pre-specified, it's a pre-specified analysis that we'll be looking at, definitely. How do the patients compare to the other anti-amyloid antibodies? You know, really right down the middle, I would say.

Speaker Change: On our end I think we mentioned this in the call in CSF <unk> and FCB won.

Speaker Change: At all of those doses. So yes, we do think that those are potentially therapeutic.

Speaker Change: In terms of the <unk>.

Alex Stranahan: Alex this.

Alex Stranahan: So we will look at each dose versus placebo, but we will also be pulling data and in fact, the top two doses.

Speaker Change: Our.

Alex Stranahan: Our overlapping considerably in their PK.

Speaker Change: So that's definitely part of R. R.

Speaker Change: Pre specified a pre specified analysis that we will be looking at.

Gary Romano: How do the patients compare to the other anti-amboid antibodies? You know, really, right down the middle, I would say. I mean, the centeloid level is a bit higher than an A-size Lequembee, but is a little bit lower than what they saw in the Nanomab; the same thing for the distribution of clinical diagnosis. And, you know, based on the data we had, it really looked right down the middle. So, we were very pleased with that. And I think the last question was, does the entire range of, oh, yeah, dosing, right, right. So, I think you're asking about with the duration of 48 weeks, be enough.

Speaker Change: Definitely.

Speaker Change: How did the patients compare to the.

Speaker Change: To the other other.

Speaker Change: If amyloid antibodies.

Speaker Change: Really right down the middle I would say.

Gary Romano: I mean, the centelloid level is a bit higher than an A-size Lekembe, but it's a little bit lower than what they saw in Denanamab. The same thing for the distribution of clinical diagnosis. And, you know, based on the data we had, it really looked right down the middle. So we were very pleased with that.

Speaker Change: This NOI level is a bit higher than size.

Speaker Change: Can be but it's a little bit lower than that.

Speaker Change: What they saw in <unk> the same thing for the distribution of clinical.

Speaker Change: Agnosis and based on the data, we hadn't really looked right down the middle so.

Speaker Change: We were very pleased with that and.

Gary Romano: And I think the last question was, does the entire range of, oh, yeah, dosing, right, right? So I think you're asking about, would the duration of 48 weeks be enough? You know, one of the reasons for the common close design here was that this is a novel mechanism.

Speaker Change: And I think the.

Speaker Change: The last question was does the entire range.

Speaker Change: Dosing right right. So.

Speaker Change: I think youre asking about with the duration of 48 weeks be enough.

Gary Romano: You know, you know, this is one of the reasons for the common closed design right here was that this is a novel mechanism, and we can't necessarily expect that the temporal dynamics and treatment effects of restoring microglial function will all happen at the same time, right. I mean, if there are effects on clearing amyloid and synapses, we might expect those earlier. If there's effects by restoring the maintenance functions of supporting, you know, the all-get-enter sites and astro sites and the brain barrier and the vasculature and immune tolerance, those could take potentially, potentially could take longer.

Speaker Change: Yes. This is one of the reasons for the common close design here was that.

Gary Romano: And we can't necessarily expect that the temporal dynamics and treatment effects of restoring microglial function will all happen at the same time, right? For example, if there are effects on clearing amyloid and synapses, we might expect those earlier. If there are effects by restoring the maintenance functions of supporting, you know, the oligodendrocytes and astrocytes and the blood-brain barrier and the vasculature, immune tolerance, those could potentially, they potentially could take longer. So, you know, we do think that 48 weeks, we should, you know, we hope to see something at 48 weeks.

Speaker Change: This is a novel mechanism and we cannot necessarily expect that that the temporal dynamics with treatment effects of restoring microglia function.

Speaker Change: It all happened at the same time Brian.

Speaker Change: If there are effects on clearing amyloid and Senate synapses, we might expect those earlier if there is.

Speaker Change: <unk> bye bye bye restoring the maintenance functions of supporting.

Speaker Change: I'll get Andrew sites and astrocytes in the blood brain barrier in the vasculature.

Speaker Change: Those could take potentially potentially it could take longer so.

Gary Romano: So, you know, we do think that 48 weeks, we should, you know, we hope to see something at 48 weeks. We will have data out to 96. And that's one of the reasons we and Abby really wanted to invest in the. In the long-term extension to be blinded to treatment assignments, so that we could get meaningful data even after, you know, even after the double blind, we'll have to double the study in the double blind. So, you know, I think some of those manifestations could be early, but we think that the full effect of this mechanism may, you know, it's possible that we that'll take longer to see that.

Speaker Change: We do think that 48 weeks, we should we hope to see something at 48 weeks.

Gary Romano: We will have data out to 96. And that's one of the reasons we and AbbVie really wanted to invest in the long-term extension to be blinded to treatment assignments so that we could get meaningful data even after, you know, even after the double blind, we locked the study in the double blind. So, you know, I think some of those manifestations could be early, but we think that the full effect of this mechanism may, you know, it's possible that we'll take longer to see that.

Speaker Change: We'll have data out to 96 and Thats one of the reasons, we and Abbvie really.

Speaker Change: I really wanted to invest in the.

Speaker Change: In the long term extension to be blinded to treatment assignment, so that we could get meaningful data even after.

Speaker Change: After the double blind we locked it.

Speaker Change: The study in the double blind so.

Gary Romano: Hopefully, we'll get to see that in those that have data out to 72 weeks and even those out to 96. But you know, if it's emerging, we'll, we'll, we have the study designed to be able to capture it makes sense. Thank you. One moment for our next question. And our next question comes from Ananda Ghosh with HC Wainwright and Company.

Speaker Change: I think some of those modifications could be early but we think that the full effect of this mechanism.

Speaker Change: It is possible that that will take longer to see that hopefully will get to see that in and those that we have data out to 72 weeks and even those out to 96, but.

Gary Romano: Hopefully, we'll get to see that in those that we had data out to 72 weeks and even those out to 96. But, you know, if it's emerging, we'll, we have the study designed to be able to capture that. Make sense. Thank you. Thanks.

Speaker Change: If thats emerging.

Speaker Change: We have the study designed to be able to capture that.

Speaker Change: Makes sense. Thank you.

Unknown Executive: One moment for our next question. And our next question comes from an ad that goes with HC Wayne Wright and Company. Hi, thanks for taking a question. I have a couple of questions. The first one is, of course, on the type meeting. So, you know, just curious given if it is encouraging stand in the Hunter syndrome. You know, where they might consider heaven itself as a surrogate biomarker, or if you look at a list, the two first on example, which, which you mentioned. What has been what has been your like takeaway like how open FEMIP to consider some of the biomarkers like pro grade union itself as the surrogate biomarker for the future and program going forward.

Speaker Change: One moment for our next question.

Speaker Change: And our next question comes from Ananda Gauche with H C Wainwright and company.

Ananda Ghosh: Yeah, hi, thanks for taking the question. I have a couple of questions. The first one is, of course, on the type B meeting. So, you know, just curious, given FDA's encouraging stand in the Hunter syndrome, you know, where they might consider heparin sulfate as a surrogate biomarker, or if you look at ALS, the Tuferson example, which, which you mentioned, you know, what has been what has been your, like, takeaway, like how open FDA might be to consider some of the biomarkers like Procradulin itself as the surrogate biomarker for the PDRN program going forward?

Ananda Gauche: Yeah, Hi, thanks for taking the question.

Ananda Gauche: Couple of questions. The first one is of course on the type B meeting. So just curious given if it is.

Ananda Gauche: Engraving stand in Hunter syndrome.

Speaker Change: They might consider heparin sulfate as a surrogate biomarker or if you look at the two funds.

Speaker Change: An example, which which you mentioned.

Speaker Change: What has been what has been your.

Speaker Change: I would like to takeaway and make whole open API might be to consider some of the biomarkers like probe gradually as the surrogate biomarker.

Speaker Change: <unk> drilling program going forward.

Unknown Executive: Yeah, thank you. I agree with you that there's been a lot of, I think there's been some regulatory flexibility, and certainly when it comes to rare diseases that they seem to have been more so, more flexibility in how they, and especially in considering biomarkers to be supportive or even enough for an approval. And you gave some good examples. You know, we're encouraged by that, but we are still, we still feel that we have, we have a very good shot at a full approval with the more traditional approach. That said, you know, if we're disappointed somehow with the clinical outcome measure here, which, you know, we think we are going to have a really good backup plan.

Speaker Change: Yes. Thank you.

Gary Romano: Yeah, thank you. I agree with you that there's been a lot of, I think there's been some regulatory flexibility and, certainly, when it comes to rare diseases, that they seem to be more, you know, more flexible in how they consider, you know, biomarkers to be supportive, or even enough for an approval. And you gave some good examples.

Speaker Change: I agree with you that theres been a lot of.

Speaker Change: I think there's been some regulatory.

Speaker Change: Flexibility and.

Speaker Change: And certainly when it comes to rare diseases.

Speaker Change: They seem to be more marceau.

Speaker Change: More flex more more flexibility in how they.

Speaker Change: And especially in considering biomarkers to be supportive or even enough for an approval.

Speaker Change: And you gave some good examples.

Ananda Ghosh: You know that we're encouraged by that, that doesn't, but we still feel that we have a very good shot at full approval with the more traditional approach. That said, you know, if we're disappointed somehow with what the clinical outcome measure here, which, You know, we think we are going to have a really good backup plan, you know, to if we see biomarker changes, as we expect to see.

Speaker Change: We're encouraged by that that does it but we are still we still feel that we have we.

Speaker Change: We have a very good shot at a full approval.

Speaker Change: With a more traditional approach.

Speaker Change: That said.

Speaker Change: If we're disappointed somehow with the clinical outcome.

Speaker Change: Measure here, which.

Ananda Ghosh: So, you know, I think we are, you know, encouraged by that, that flexibility, but, but, you know, a full approval for us is, you know, is, it's not debatable. It's like, you know, it would be better for patients, better for us if we could get a full approval.

Speaker Change: We think we're going to have a really good backup plan.

Unknown Executive: You know, if we see biomarker changes as we expect to see. So, you know, I think we are, we are encouraged by that flexibility, but, you know, a full approval for us is, you know, it's not debatable. It's like, you know, it would be better for patients, better for us if we can get a full approval.

Speaker Change: If we see biomarker changes as we expect to see so.

Speaker Change: I think we were encouraged by that that flexibility, but but.

Speaker Change: Full approval for us is.

Speaker Change: <unk>.

Speaker Change: As Dr.

Dr.: Not debatable.

Speaker Change: It would be better for their patients better for us if we can.

Unknown Executive: Got it. You know, a follow-up question on the program in program is at the European L.S. conference, you know, a lot of course, K. Wells actually pointed out that, and now it's kind of well established in case of professor. You see the NFL drop much before then, you know, then you see the clinical benefit coming from professor in S.O.D.1, mutant patients. So, you know, for your program in program, have you thought about thought like, is there a way to kind of to also track that where, where you see the clinical benefits kind of lags behind the drop in, you know, some of the key biomarkers or the way the biomarkers are progressing.

Speaker Change: Could you get a full approval.

Gary Romano: A follow-up question on the progranulin program is, at the European ALS conference, a lot of KOLs actually pointed out that, and this is now kind of well-established, in the case of TOFILSYN, you see the NFL drop much before you see the clinical benefit coming from TOFILSYN in SOD1 mutant patients. So for your progranulin program, is there a way to also track where you see the clinical benefits kind of lag behind the drop in some of the key biomarkers or the way the biomarkers are progressing? Yes, Thank you.

Speaker Change: Got it a follow up question on the programming program is.

Speaker Change: At the European Analyst Conference and a lot of Kols actually pointed out that and now it's kind of well established in case of Tofacitinib.

Speaker Change: You will see that drop much before then.

Speaker Change: And then you'll see the clinical benefit coming from Hudson City, one mutant patients so.

Speaker Change: For your pro granular in our program having portable.

Speaker Change: Like is there a way to kind of.

Speaker Change: We will also track that we have.

Speaker Change: You will see the clinical benefits kind of lags behind.

Speaker Change: The drop in some of the key biomarker.

Speaker Change: Davita Biomarkers.

Unknown Executive: Yeah, yeah, I agree with you. And we, you know, the same is true in F in F.T.D. You see changes in NFL before you see clinical, clinical science and symptoms. That's why in our study, we originally started out, including patients who were asymptomatic, but we knew that we're at risk because they had a program when also function mutation and they also had elevated NFL levels. We originally planned to include in our primary analysis, but, but because they were they're hard to find and we did very fewer of them and because they had a lot of variability to the, to the, you know, to, to progression rates.

Ananda Ghosh: Yeah, yeah, I agree with you. And we, you know, the same is true in FTD. You see changes in NFL before you see clinical signs and symptoms. That's why, in our study, we originally started out including patients who were asymptomatic, but we knew they were at risk because they had a progranulin loss of function mutation, and they also had elevated NFL levels. We originally planned to include it in our primary analysis, but because they were hard to find, and we had very fewer of them, and because they add a lot of variability to the So, you know, we think if it's going to work in symptomatic patients, it may work even better in the early patients and in the pre-symptomatic patients.

Speaker Change: <unk>, yes, yes.

Speaker Change: I agree with you.

Speaker Change: The same is true in an FTE you see changes in NFL before you see clinical clinical.

Speaker Change: Clinical signs and symptoms.

Speaker Change: That's why in our study we originally started out.

Speaker Change: <unk> patients who were asymptomatic, but we knew that we are at risk because they had for granular and loss of function mutation and they also had elevated Nf L levels.

Speaker Change: We originally plan that included in our primary analysis, but.

Speaker Change: But because they were they're hard to find and we got many fewer of them and because they add a lot of variability to the to be.

Speaker Change: Two two progression rates.

Unknown Executive: We last year we went to FDA and EMA and we proposed to focus on the symptomatic patients for the primary analysis, but we will still analyze that data in the presymptomatic patients as a sensitivity analysis. So, and we're very excited about that. You know, we think if it's going to work in symptomatic patients, who may work even better in the early patients and the presymptomatic patients. So, you know, and yeah, we, you know, we may, we'll see when we look at our data, but whether we see changes in NFL that proceed. Yeah, you know, the temper of dynamics of effects on those biomarkers versus the clinical outcomes.

Speaker Change: We last year, we went to FDA and EMA and we proposed to focus on the on the on the symptomatic patients for the primary analysis, but we will still analyze that.

Speaker Change: Data in the pre symptomatic patients is a sensitivity analysis.

Speaker Change: And we're very excited about that we think if it is going to work in symptomatic patients who may work, even better and the early patients in the pre symptomatic patients. So.

Ananda Ghosh: So, you know, and yeah, we may, we'll see when we look at our data, whether we see changes in NFL that precede, you know, the temporal dynamics of effects on those biomarkers versus a clinical trial.

Speaker Change: And yes, we may well see when we look at our data whether we see changes in NFL that precede.

Speaker Change: Yes.

Speaker Change: Yes.

Speaker Change: Yes.

Speaker Change: The central dynamics of effects on those biomarkers versus the clinical outcomes.

Ananda Ghosh: Got it. And I just have two questions on the TREM-2. The first one is, you know, both Biogen and, obviously, Lilly have done this low tau, high tau-like analysis for their AD trials. So what have you, like, do you have plans to kind of do a subgroup analysis later on where you are looking at low tau or high tau to kind of figure out what the L002 impacts in this kind of population? And the second question is how fast the ramp-up might be for your titration schedule for L002.

Unknown Executive: Courtney, and I just have two questions on the trim too. The first one is, you know, both Biogen and, obviously, Lily has done this, you know, the low tau, how tau, like, high tau, like, analysis for their 80 trials. So what, have you, like, do you have plans to kind of do a subgroup analysis later on, where you are looking at low tau or high tau, and to kind of figure out what, you know, how the L002 impacts in this kind of population. And the second is how fast the ramp app might be for your titration schedule for AL002?

Speaker Change: Got it.

Speaker Change: I just have two questions on the <unk>. The first one is.

Speaker Change #106: Both biogen and obvious.

Speaker Change: Lilly has done this the lot our hotel like on a high touch high Tech like analysis.

Speaker Change: For the 80 trials. So what have you like do you have plans to kind of do a subgroup analysis later on where you are looking at our hydro.

Speaker Change: In the two to kind of figure out what how.

Speaker Change: <unk> total impact in this kind of population and the second is how fast the ramp up might be forward your titration schedule for <unk>.

Gary Romano: Yeah, so, okay. So, about the tau, a question about, you know, will you use tau tertiles? Yeah, yeah, we, that's definitely part of our pre-specified analysis. We're going to, we will have P217 at, at, in every, in every patient, so we can do it by P217 levels. We will also have tau PET in a smaller subset, but we'll be doing it mostly based on plasma, plasma P-tau markers. We are going to look at those tertiles.

Gary Romano: Yeah, so, okay, so about the how, a question about, you know, will you use tau, terciles? Yeah, yeah, we, that's definitely part of our pre-specified analysis. We're going to, we will have P217 at every, in every patient, so we can do it by P217 levels. We will also have tau pet in a smaller subset, but we'll do it mostly based on plasma, plasma, plasma p-town markers. We are going to look at those terciles. That, of course, will tell us what we give us some indication of whether we are seeing, we are seeing differential effects across the disease spectrum, you know, in low tau or mid-tau patient, or high-tau patients.

Speaker Change: Yes, so okay. So.

Speaker Change: About the.

Speaker Change: Question about really Tao <unk>, yes, yes, that's definitely part of our pre specified analysis, we're going to we will have pizza $1 seven at.

Speaker Change: And every patient so we can do it by <unk> seven levels. We've also tau pet in a smaller subset, but we'll be doing it mostly based on plasma plasma <unk> markers. We are going to look at those for sales that of course will tell us will give us some indication of whether we are.

Gary Romano: That, of course, will tell us, will give us some indication of whether we are seeing differential effects across the disease spectrum, you know, in low tau and mid tau patients or high tau patients. That said, we really don't expect to see these differences as much with this mechanism than we would with an anti-AMLID antibody, where there's more of a defined window of the pathophysiology where it may work best.

Speaker Change: We are seeing.

Speaker Change: We are seeing dip.

Speaker Change: Differential effects across the disease spectrum and low tower, that's how patient are high top patients.

Gary Romano: That said, we really don't expect to see these differences as much with Michael, with this mechanism, than you would with an anti-amoled antibody, where there's more of a defined window of the pathophysiology that we're, it may work the best. The question, the second question, is about the ramp up. So, you know, we are, in our study, when we went to a titration, it was every four weeks was the increase in, in dose, and that's why we, as I mentioned earlier, that we were putting in MRI surveillance. We're lower dose in, in the patients that roll over in the LTE, because we want to learn whether that could be mitigating for the area.

Speaker Change: We really don't expect to see these differences as much with Michael with this mechanism than you would with a with an anti amyloid antibody, where theres more of a defined window the past physiology that where it may work the best.

Gary Romano: The second question is about the ramp-up. So, you know, in our study, when we went to titration, it was every four weeks an increase in dose. And that's why we, as I mentioned earlier, are putting in MRI surveillance. We're slowing that titration down and starting at a lower dose in the patients that roll over in the LTE because we want to learn whether that could be mitigating for the IRA.

Speaker Change: Second question is about the ramp up.

Speaker Change: So.

Speaker Change: In our study.

Speaker Change: When we went to a titration was every four weeks, whereas the increase in dose and that's why we as I mentioned earlier that we were.

Speaker Change: Sure.

Speaker Change: Putting an MRI surveillance, we're slowing that titration down and starting at a lower dose in the patients that rollover in the LTE, because we want to learn whether that could be mitigating for the area.

Unknown Executive: Okay, thank you very much.

Speaker Change: Okay.

Unknown Executive: Thanks, and out of good questions.

Speaker Change: Okay.

Ananda Ghosh: Thanks, Ananda, good questions. I think we have time for two more here. One moment.

Speaker Change: Thanks, a lot of good questions. Operator, I think we have time for I think for.

Gregory Harrison: I pray I think we have time for two more here. One moment for our next question. Our next question is from Greg Savanovic, with Mizo Securities. Thank you very much for taking my question, and congrats on the progress.

Speaker Change: Two more here.

Operator: One moment for our next question. Our next question is from Greg Suvannavejh with Mizzou Security.

Speaker Change: One moment for our next question.

Speaker Change: Our next question is from Greg Savannah, <unk> with Mizuho Securities.

Greg Suvannavejh: Thank you very much for taking my question and congratulations on the progress. Earlier in your prepared remarks, you had mentioned, I think, the analytical methodology that you will apply to the trial. You were invoked to trial, and I wanted to ask about how that particular methodology might compare with others in Alzheimer's disease. It does seem as if you've taken an innovative approach here with the view that you're hoping to increase the power of the study, but as someone who may not be as well-versed in that methodology, could you just speak to the differences between how others have analyzed their Alzheimer's trials?

Greg Savannah: Thank you very much for taking my question and congrats on the progress.

Gregory Harrison: Earlier in your preparatory remarks, you had mentioned, I think, the analytical methodology that you will apply to, you were invoked to trial, and I wanted to ask about how that particular methodology might compare with others in Alzheimer's disease. It does seem as if you've taken an innovative approach here with the view that you're hoping to increase the powering of the study, but someone who may not be as well-versed in that methodology, could you just speak to, you know, the differences between how others have analyzed their Alzheimer's trial. Thanks. Yeah, yeah, so this this proportional method that we're using or proportional MMORM, as I mentioned, you know, it's it allows us to look at we it allows you to it's really particularly helpful in in the common close design where we have patients at different with different durations of treatment and we can use all of that data as I outline.

Gary Romano: Thanks.

Speaker Change: Earlier in your prepared remarks, you had mentioned I think a analytical methodology that you will apply to.

Speaker Change #106: You were invoked to trial and.

Speaker Change #103: I wanted to ask about how that particular methodology might compare with others in Alzheimer's disease. It does seem as if you've taken an innovative approach here with the view that youre, hoping to increase the powering of the study, but someone who may not be as well.

Speaker Change: <unk> in that methodology could you just.

Speaker Change #106: Speak to.

Speaker Change #106: The differences between how others have analyze their Alzheimer's trials. Thanks.

Gary Romano: Yeah, yeah. So, this proportional method that we're using, or proportional MMRM, as I mentioned, it allows us to look at, it allows you to, it's really particularly helpful in the common close design, where we have patients with different durations of treatment, and we can use all of that data, as I outlined. This is a novel method, but it has been used before in Alzheimer's trials. In one of the DIAN studies, it was used, and also, I believe that they really used it as a sensitivity analysis in NeuroFERI phase two and possibly one, ASI, I'm not, I don't remember which study that was.

Speaker Change #101: Yes, yes so.

Speaker Change #105: This proportional method that we're using our proportional MRM.

Speaker Change #101: As I mentioned.

Speaker Change #101: It allows us to look at.

Speaker Change #101: Lastly, it's really particularly helpful. In the common close design, where we have patients with different with different durations of treatment and we can use all of that data as I outlined.

Gary Romano: This is a this is a novel method, but it has been used before in Alzheimer's trials in one of the Diane studies it was used and also I believe that that I'm really used it in as a since hitting out in their fair space to and possibly want a site I'm not I don't remember which study that was so it's it's it is novel but others have have explored it. Yeah, I think it's it for us we thought given the common close design and given that we were trying to make this a really a biomarker rich study we would have a lot of different types of readouts we thought this would be, you know, the best really and and I should say Abby, you know, agreed around this design you know, some years ago before the study started. So, yeah, we will also do sensitivity analysis with other with other more traditional approaches but but this is our primary outcome.

Speaker Change #101: This is this is a novel method, but it has been used before in Alzheimer's trials one of the Diane studies. It was used and also I believe that.

Speaker Change #106: Really use it.

Speaker Change #101: Sensitivity analysis in their first phase II.

Speaker Change #101: Possibly want ACI I don't remember.

Gary Romano: So, it's, it's, it is novel, but others have explored it. Yeah, I think it's, for us, we thought, given the common close design and given that we were trying to, you know, make this a really, a biomarker-rich study, we would have a lot of different types of readouts, we thought that this would be, you know, the best. And I should say, Abby and I agreed on this design some years ago, before the study started. So, so, Yeah, I mean, we'll also do sensitivity analysis with other more traditional approaches, but this is our primary, Thanks for the question.

Speaker Change #101: Which study that was.

Speaker Change #101: So.

Speaker Change #101: It is novel, but others have explored it.

Speaker Change: Yes, I think.

Speaker Change #101: For us we thought given the common close design and given that we were trying to.

Speaker Change #101: This is really a biomarker rich study, we would have a lot of different types of readouts, we thought that this would be.

Speaker Change #101: The best really.

Abbvie: I should say abbvie.

Abbvie: Agreed around this design.

Abbvie: Some years ago before the study started so so.

Abbvie: Yes, I mean, we will also do sensitivity analysis with other with other more traditional approaches but this is our primary outcome.

Corinne Jenkins: Thanks for the question, Greg. Operator, I think we have time for one more. Our next question then comes from Korean Johnson with Goldman Sachs. Yeah, thanks, guys. Good afternoon.

Greg Suvannavejh: Thanks for the question, Greg. I think we have time for one more. Our next question then comes from Corinne Johnson with Goldman Sachs. Yeah, thanks, guys. Good afternoon.

Abbvie: Okay. Thanks for the question, Greg Hi, Brian I think we have time for one more.

Corinne Johnson: Our next question then comes from Corinne Johnson with Goldman Sachs. Yeah, thanks, guys. Good afternoon.

Speaker Change #105: Our next.

Speaker Change #105: Then comes from Corinne Johnson with Goldman Sachs.

Gary Romano: Maybe could you just talk a little bit, I think I understand, but if you could just like square the comments you've made around thinking the mechanism is related to amyloid clearance but that you don't have to get the same degree of centroid reduction, you're going to see clinical effects. And then maybe you could expand a little bit more on the cash runway guidance, particularly with respect to which activities around the ABC platform are going to be embedded within that timeframe. Yeah, so I'll take the first one, Corinne.

Corinne Johnson: Yes, thanks, guys.

Corinne Jenkins: Maybe could you just talk a little bit? I think I understand, but if you could just explore the comments you've made around thinking the mechanism is related to amyloid clearance. But you don't have to get the same degree of dental introduction; they're going to see clinical effect, and then maybe you could extend a little bit more on the cash one-way guidance, particular with respect to which activities around the ABC platform we're going to be embedded within that time frame. Yeah, so I'll take the first one current, thanks for good good question. Yeah, so what I was referring to is that so our hypothesis is that increasing trim to signaling triggers a number of other signaling pathways that call allow for a proforation of microglia, increased function and survival. And we think that this is going to shift the population of microglia. We know that with aging and with neurodegenerative disease, you have some essence of microglia, so by shifting the microglia to more healthy.

Corinne Johnson: Good afternoon.

Corinne Johnson: Could you just talk a little bit I think I understand but if you could just square the comments you've made around containment mechanism as it related to the amyloid clearance, but you don't have to get the same degree of central introduction I can see clinical effect.

Speaker Change #100: And then maybe you could expand a little bit more on the cash runway guidance, particularly with respect to which activities around the ABC platform are going to be embedded within that timeframe.

Gary Romano: Thanks. Good question. Yeah, so what I was referring to is that, our hypothesis is that increasing TREM-2 signaling triggers a number of other signaling pathways that allow for,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, They would clear TDP-43, and they would clear other alpha-synucleins and the like. So, you know, we think this is why we're so excited about this mechanism.

Speaker Change #112: Yes, so I'll take the first one current thanks very.

Speaker Change #113: Good question, yes, so what I was referring to is that.

Speaker Change #100: So.

Speaker Change #106: Our hypothesis is that <unk>.

Speaker Change #122: Decreasing from two signaling.

Speaker Change #100: Triggers a number of other signaling pathways that.

Speaker Change #106: Now for.

Speaker Change #106: Proliferation of microglia.

Speaker Change #106: Increased function and survival and we think that this is going to shift the population of my quickly, we know that with aging and with Neurodegenerative disease, you have senescence might quickly, yes, so by shifting the microglia to more healthy.

Arnon Rosenthal: And active and functional microglia will have that all those beneficial effects that come you know won't repeat that you know that that come from microglia including including amyloid clearance and clearance of misfolded proteins. And by the way, it's interesting that it we're focused not on amyloid because of the potential. The area like signal but you know there's lots of comorbidities that are usually seen with Alzheimer's disease so microglia are not, you know, are not selective for amyloid they would clear TDP 43 and they would clear other the authentically in and the like. So, you know, we think this is a, you know, this is why we're so excited about this mechanism when I say it, you know, it doesn't need to reach the 24 cent o'clock level I think for an anti amyloid antibody.

Speaker Change #100: <unk> active in functional microglia.

Speaker Change #100: All of those beneficial effects that come what may.

Speaker Change #118: Repeat that.

Speaker Change #100: That's come from microglia.

Speaker Change #100: Including including amyloid clearance and clearance of Misfolded proteins and by the way it's interesting.

Speaker Change #100: We're focused not on amyloid because of the potential of the area like signal, but theres lots of Comorbidities that are usually seen.

Speaker Change #113: Househunters disease.

Speaker Change #113: So.

Speaker Change #113: Or not.

Speaker Change #113: We are not selective for amyloid they would clear TDP 43, and they would clear other.

Speaker Change #112: Cynically and the like so so we think this is.

Speaker Change #100: This is why we're so excited about this mechanism.

Gary Romano: When I say, you know, it doesn't need to reach the 24 centeloid level; I think for an anti-amyloid antibody, that's what it does. It lowers amyloid. It looks like there's now plenty, lots of data showing that curve. You've seen the graphs, I'm sure, where it shows that.

Speaker Change #112: When I say it.

Speaker Change #113: Doesn't need to reach the 24 satellite level I think for an anti amyloid antibody, where that's that's what it does it lowers amyloid it looks like Theres now plenty of lots of data showing that <unk> seen these graphs I'm sure will show that.

Arnon Rosenthal: That's, that's what it does; it lowers amyloid. It looks like there's now plenty of lots of data showing that curve. You've seen the graphs, I'm sure, where to show that. You need to get to a certain level before you start seeing clinical benefit. I mean, the, um, the, uh, Gantan Aramab study is an example of one that didn't quite get there. And, and, you know, in Atticat, and I had, you know, one of the studies didn't get there. It didn't have clinical; the clinical data were less robust. So it looks like you have to get down to this 24-centaway level, uh, if that's your mechanism you're using.

Gary Romano: You need to get to a certain level before you start seeing clinical benefit. I mean, the Gantanerumab study is an example of one that didn't quite get there. And, you know, in Atacatumab, one of the studies didn't get there, didn't have clinical data that were less robust. So it looks like you have to get down to this 24 centiloid level if that's the mechanism you're using.

Speaker Change #113: You need to get to a certain level before you start seeing clinical benefit.

Speaker Change #113: <unk>.

Speaker Change #113: The <unk> study as an example of one that didn't quite get there.

Speaker Change #100: Advocated that one of the studies didn't get there it didn't have clinical the clinical data were less robust. So it looks like you have to get down to that 24 satellite level.

Speaker Change #113: If thats your mechanism using this mechanism goes beyond that yes, we might have amyloid clearance, but.

Gary Romano: This mechanism goes beyond that. Yes, we might have amyloid clearance, but we think that all of these downstream mechanisms are at play. And so, you know, we're not going to judge this mechanism of action based just on the amyloid clearance, the amount of amyloid clearance. You hope that that helped? Did that help? Yes. Yeah. I can add to this a little bit.

Arnon Rosenthal: This mechanism goes beyond that. Yes, we might have amyloid clearance, but we think that all of these downstream mechanisms are at play. And, and so, you know, we're not going to judge this mechanism of action based just on the amyloid clearance, the amount of amyloid clearance we see. I hope that, did that, did that help, or did I answer that?

Speaker Change #100: But we think that all of these downstream mechanisms are at play and so we're not going to judge this mechanism of action based just on the amyloid clearance.

Speaker Change #113: Mount of amyloid clearance, we see hope that does that.

Arnon Rosenthal: There are data even in humans that Microglia, in a tram-to-dependent manner, can contain A-beta without removing it. They form a barrier between the A-beta plaques and the surrounding neurons, and they basically make the A-beta plaques inert. The A-beta plaques can no longer injure the neurons, so you can get therapeutic benefit even on A-beta without removal of A-beta if you recruit the microglia. And in addition, yes, as Gary said, the microglia are responsible for the replacement of damaged synaptic connections.

Arnon Rosenthal: Yeah, I can add to this, yeah. I can add to this a little bit, there are data even in human that a microglia in a trying to dependant manner can contain a beta without removing it. They form a barrier between the a beta plaques and the surrounding neurons, and they basically make the a beta plaques inert, and a beta plaques can no longer injure the neurons. So, so you can get therapeutic benefit even on a beta without removal of a beta if you recruit the microglia. I see. And in addition, yes, as Gary said, the microglia responsible for replacement of damaged synaptic connections in Alzheimer's disease, up to 50 percent of the synapses can be damaged.

Speaker Change #100: Did I answer yes.

Speaker Change #100: Ed.

Speaker Change #121: Yeah, I can add to this a little briefly.

Speaker Change #129: Even in human.

Michael <unk>: Hey, Michael.

Michael <unk>: I am too dependent.

Michael <unk>: Kevin.

Michael <unk>: Without removing it they form a barrier between the ABB tap blocks.

Speaker Change #100: Rounding neurons.

Speaker Change #100: Basically make the black sea.

Speaker Change #100: <unk> no longer in general the neurons.

Speaker Change #114: So you can get therapeutic benefit even on a beat that without the removal of a beat that for you.

Speaker Change #100: Michael.

Speaker Change #119: Okay. Okay.

Speaker Change #119: In addition, we have.

Speaker Change #100: Gary said, the microglia responsible for replacement of Diamond synaptic connections in Alzheimer's disease up to 50% of the Synopsys can be damaged.

Arnon Rosenthal: In Alzheimer's disease, up to 50% of the synapses can be damaged. They are responsible for the replacement of damaged myelin. There is significant myelin damage in Alzheimer's disease. They are responsible for direct neural transmission. Without functional microglia, neural transmission is abnormal. So there are a lot of other activities that should translate to clinical benefit independent of beta pathology.

Arnon Rosenthal: They are responsible for the replacement of damage mildly in the significant mildly in damage in Alzheimer's disease. They are responsible for direct neural transmission; without functional microglia, neural transmission is abnormal. So, there are a lot of other activities that should translate to clinical benefit independent of a beta pathology.

Gary: Were responsible for the replacement of damage Miami very quickly if you could.

Gary: Myelin damage in Alzheimer's disease.

Gary: Consequent full direct normal transformation without functional microglia novel transmission is not the norm.

Gary: There are a lot of other activities that should translate to clinical benefit independent of a beta pathology.

Unknown Executive: And just on the cash runway, guys, it's Corinne. So we reiterated that our runway is through 2026, and that's, you know, a full two years beyond the expected TRIM 2 data readout end of this year and, you know, a full year beyond the expected FTD Phase 3 readout end of next year, and doesn't assume any opt-in from AbbVie or, you know, other milestones So, you know, we think that's a pretty healthy runway and a strong position as it relates to the electrobrain carrier portfolio.

Marc Grasso: And just on the the cash runway, guys, Karin.

Unknown Executive: I'm just on the cash runway, guys.

Speaker Change #124: And just on the cash runway guidance Korean so we reiterated that our runway through 2026.

Marc Grasso: So, we reiterated that our runways through 2026 and that's, you know, a full, you know, two years beyond expected trim two data readout. And the this year and, you know, a full year beyond expected FTD phase three readout and a next year and doesn't assume any opt-in from Abby or, you know, other milestones or business development.

Speaker Change #122: Two years be unexpected <unk> data readout end of this.

Gary: This year and our full year be unexpected FTE.

Speaker Change #122: TD phase III readout end of next year and does not assume any opt in from Abbvie.

Speaker Change #100: Are there milestones are our business development. So we think thats, a pretty healthy runway in a strong position as it relates to the electric brain carrier portfolio, we're going to provide more updates as that program progresses.

Unknown Executive: We're going to provide more updates as that program progresses, as those programs progress. We haven't said specifically what that would advance those programs through, but, you know, you could expect that that would be, you know, through INDs on programs.

Marc Grasso: So, you know, we think that's a pretty healthy runway, and the strong position is a relates to the electric brain carrier portfolio.

Marc Grasso: We're going to provide more updates; is that program progress? Is where those programs progress. We haven't said specifically what that would advance this program through, but, you know, you could expect that that would be, you know, through INDs on programs. Okay, thank you. Yeah.

Speaker Change #122: Those programs progress, we haven't said specifically.

Speaker Change #124: What that would.

Speaker Change #100: Advances programs through but you could expect.

Speaker Change #100: That that would be through <unk> on programs.

Speaker Change #123: Okay. Thank you.

Speaker Change #100: Yes.

Operator: And this concludes the question-and-answer session.

Operator: And that concludes the question and answer session. I would now like to turn it back to Marc for his closing remarks.

Speaker Change #100: And this concludes the question and answer session I would now like to turn it back to Mark for his closing remarks.

Marc Grasso: I would now like to turn it back to Mark for closing remarks. Thanks everyone for the thoughtful questions.

Marc Grasso: Thanks, everyone, for the thoughtful questions. Before we end the call, I'd just like to share that we will be participating in a number of upcoming conferences, including the Morgan Stanley Annual Global Health Care Conference on September 5th in New York, HD. Wainwright's Global Investment Conference on September 9th in New York, and Cantor's Global Health Care Conference on September 17th in New York. Thank you again for your time and attention.

Mark: Thanks, everyone for that.

Marc Grasso: Before we end the call, I'd just like to share. We will be participating in a number of upcoming conferences, including the Morgan Stanley Annual Global Health Care Conference September 5th in New York, H.U.A. and Rice Global Investment Conference on September 9th in New York and Canter's Global Health Care Conference on September 17th in New York.

Mark: The thoughtful questions before we end the call I'd just like to share we will be participating in a number of upcoming conferences, including the Morgan Stanley Annual Global Healthcare Conference September five in New York HC Wainwright Global investment Conference on September 19th in New York and Cancerous Global Healthcare Conference on September 17th in New York. Thank you.

Operator: And thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

Marc Grasso: Thank you again for your time and attention today.

Speaker Change #100: And for your time and attention today.

Operator: And thank you for your participation in today's conference.

Speaker Change #124: And thank you for your participation in today's conference. This does conclude the program you may now disconnect.

Operator: This does conclude the program. You may know this.

Operator: Okay, now we'll stop.

Operator: Good bye.

Mark: Goodbye.

Mark: Okay.

Mark: [music].

Mark: Okay.

Mark: Okay.

Mark: Yes.

Mark: Yes.

Speaker Change #100: [music].

Speaker Change #100: Yes.

Speaker Change #100: [music].