Full Year 2023 Alector Inc Earnings Call

Okay.

Operator: Good day, and thank you for standing by. Welcome to Alector's Q4 2023 Earnings Conference Call. At this time, all participants are in a listen-only mode.

Good day, and thank you for standing by.

Welcome to.

Elector.

Q4, 2023 earnings conference call.

At this time.

All participants are in a listen only mode.

Operator: 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 on your telephone; you will hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to turn the conference over to your speaker for today, Katie Hogan. Please go ahead.

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 on your telephone.

You will hear an automated message advising your hand is right.

Withdraw your question. Please press star one again.

Please be advised that today's conference is being recorded.

I would now like to her tent excuse me to turn the conference over to your speaker for today Katie Hogan. Please go ahead.

Katie Hogan: Thank you, Operator, and hello, everyone. Earlier this afternoon, we released our financial results for the fourth quarter and full year 2023. 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. Joining me on the call today are Dr. Arnon Rosenthal, co-founder and CEO; and Dr. Sarah Kankari Mitra.

Katie Hogan: Thank you operator, and Hello, everyone earlier. This afternoon, we released our financial results for the fourth quarter and full year 2023.

Speaker Change: Yes release is available on our website at Www Dot Electra Dot com.

Speaker Change: And our 10-K was filed with the Securities and Exchange Commission. This afternoon.

Katie Hogan: Joining me on the call today are Doctor Arnon Rosenthal co founder and CEO, Dr. Sarah can Karimi Trust <unk>.

Katie Hogan: President and Head of Research and Development. Dr. Gary Romano, Chief Medical Officer, and Dr. Mark Rath, Chief Financial Officer.

President and head of research and development Dr.

Katie Hogan: Dr. Gary Romano.

Katie Hogan: Chief Medical Officer.

Speaker Change: And Dr. Marc Grasso, Chief Financial Officer.

Katie Hogan: 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. I would now like to turn the call over to Arnon Rosenthal, Chief Executive Officer.

Katie Hogan: After our formal remarks, well open the call for Q&A.

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 on the webcast, which contains our forward looking statement disclosure and we also encourage you to review our SEC filings for more information.

Katie Hogan: I would now like to turn the call over to Arnon Rosenthal, Chief Executive Officer R&R.

Arnon Rosenthal: Thank you, Katie. Good afternoon, everyone. And thank you for joining Alector for our fourth quarter and full year 2023 financial results conference call. I'll begin by highlighting the broad mechanistic potential of our immunoneurology candidates. Our candidates recruit microglia, the brain's primary immune cells, to combat neurodegeneration by containing multiple classes of misfolded proteins, maintaining brain health and neuronal function, and supporting the maintenance of healthy synapses, astrocytes, oligodendrocytes, the blood-brain barrier, and the vasculature. By harnessing microglia, our candidates aim to comprehensively address the complex pathology of neurodegenerative diseases, potentially providing long-lasting clinical benefits across multiple disease stages.

Arnon Rosenthal: Thank you Katie good afternoon, everyone and thank you for joining alecto for fourth quarter and full year 2023 financial results Conference call.

Arnon Rosenthal: I'll begin by highlighting the broker is the potential for immuno neurology can be done.

Arnon Rosenthal: Our Canada recruit microglia, the brain's primary immune cells to combat the generation Brightcove.

Arnon Rosenthal: Containing multiple classes of Misfolded protein.

Arnon Rosenthal: Turning Bryan Hanson function and supporting the maintenance of healthy, it's an abscess astrocytes oligodendrocyte.

Arnon Rosenthal: The blood brain barrier and the vasculature.

Arnon Rosenthal: By harnessing microglia, our candidate aimed to compare MTBE address the complex pathology of Neurodegenerative diseases.

Arnon Rosenthal: Thankfully, providing long lasting clinical benefits across multiple disease stages.

Arnon Rosenthal: Our investigational drug candidates have the potential to be effective as stand-alone therapies or in combination with other treatments, particularly those targeting misfolded proteins. The broad disease-fighting mechanisms that our drugs activate, as well as the potential synergy between our immunoneurology candidates and therapies directed against misfolded proteins, have the potential to elicit a more potent therapeutic benefit with longer durability and better efficacy at multiple disease stages compared to As we reflect on the past year, I am pleased to highlight that 2023 was marked by successful clinical execution and clarity around timelines for our Advanced Clinical Development Program. We achieved significant milestones in our late-stage programs, reinforcing Alector's standing as a pioneer in immunoneurology. Importantly, we completed trial enrollment for our two lead programs.

Our investigational drug can be bad.

Arnon Rosenthal: The potential to be effective as standalone therapy or in combination with other treatments.

Arnon Rosenthal: Particularly those targeting misfolded proteins.

Arnon Rosenthal: The broad does this pricing mechanism that our drugs activity as well as the potential synergy between our immuno oncology candidate.

Arnon Rosenthal: Therapies directed against with further propane has the potential to elicit a more potent therapeutic benefit with longer Europe, EVP and better efficacy at multiple stages compared to current therapies or capex further proteins.

Arnon Rosenthal: As I reflect on the past year I am pleased to highlight that 2023 was marked by successful clinical execution clarity around timeline, so our advanced clinical development programs.

Arnon Rosenthal: We achieved significant milestone in our late stage program reinforcing electricals standing as a pioneer in immuno oncology.

Importantly, we completed trial enrollment for our two lead programs. These include the pivotal and <unk> phase III trial.

Arnon Rosenthal: This includes the Pivotal in Front 3 Phase 3 trial of our progranulin-elevating candidate latuzinamab in frontotemporal dementia with progranulin gene mutation, or STD-GRN, and Invok2 Phase 2 trial of our TRAM2 candidate AL002 in early Alzheimer's disease. In partnership with GSK, we also recently dosed the first participant in PROGRESS-AD, the Phase II clinical trial Furthermore, in February 2024, the FDA granted breakthrough therapy designation to latozinumab for FTD-GRN, marking another significant achievement. It is worth noting that although STD is a complex disease clinically, we have developed a straightforward approach to correcting pro-grounding deficiencies. The underlining cause of the disease.

Our programming elevating Canada Latina mob in front of petrol dementia with Borgwarner linked gene mutation or SBB GRN.

Arnon Rosenthal: Earnings walk to phase II trial of our Toronto, Canada.

Arnon Rosenthal: Zero two in early Alzheimer's disease.

Arnon Rosenthal: In partnership with GSK, We also recently dosed the first participant in progress.

Arnon Rosenthal: The phase two clinical trial of Min 101 in early Alzheimer's disease.

Arnon Rosenthal: Furthermore, in February 2020 for the FDA granted breakthrough therapy designation to retrofit.

Arnon Rosenthal: For FTP GRM, marking another significant achievement.

Arnon Rosenthal: It is worth noting that all Directv is a complex disease clinically.

Arnon Rosenthal: We have developed a straightforward approach to collecting programming deficiency.

Arnon Rosenthal: The underground.

Arnon Rosenthal: Cause of the disease.

Arnon Rosenthal: Collectively, these advancements move us closer to potential meaningful data readout this year and next. In January, we also further strengthened our balance sheet with the completion of $75 million in follow-on financing, which Mark will touch on further. Later in this call, Sarah will provide insight into our early research and development efforts, including Alector's brain carrier technology platform. Our commitment to addressing knowledge generation remains unwavering, and with our advanced pipeline, and strong cash position, we are well equipped for meaningful value creation in the next phase of our growth. This year, we'll continue to focus on delivering and translating our progress into meaningful impact.

Arnon Rosenthal: Collectively these advancements move us closer to potential meaningful data readout this year and mix.

Arnon Rosenthal: In January we also further strengthened our balance sheet with the completion of $75 million follow on financing, which mark will touch on further.

Arnon Rosenthal: Later in this call Sarah will provide insight in our area.

Research and development efforts, including directors, Brian Carryout technology platform.

Arnon Rosenthal: Our commitment to addressing the other generation remains unwavering and with our advanced pipeline strong cash position, we are well equipped for meaningful value creation in the next phase of our growth.

Arnon Rosenthal: This year, we'll continue to focus on delivering them translation translating our progress into meaningful impact.

Gary: An important event will be the anticipated data readout from the InVoC2 Phase 2 trial of L002 in the fourth quarter. This will potentially be a major step forward in elucidating our immunoneurology hypothesis. Together with the support from our partners, we are committed to advancing neurodegenerative disease research, reflecting our firm belief in immunoneurology and in immunoneurology potential. With that, I will turn it over to Gary to talk about our golden expectations for our clinical development program. Gary, Thank you, Armand.

Arnon Rosenthal: An important event will be the anticipated data readout from invoked to phase II trial of <unk> zero zero during the fourth quarter.

This will potentially be a major step forward in elucidating, our immuno oncology hypotheses.

Arnon Rosenthal: Together with the support from our partners that we are committed to advance ignore the generative disease research, reflecting our firm belief in immuno oncology and immuno neurology potential.

Speaker Change: With that I will turn it over.

Over to Gary to talk about our goals and expectations for our clinical development program.

Speaker Change: Sorry.

Gary: I'll begin with our AL002 program, the most advanced trend two program in clinical development for Alzheimer's. AL002 is a novel investigational humanized monoclonal antibody that binds to and activates TREM2, a key microglial receptor that senses pathological changes in the brain. Binding of AL002 to the TREM2 receptor triggers a microglial signaling pathway, which increases microglial perforation, survival, and function, enhancing the effectiveness of microglia to protect the brain against insults, including age-related neurodegenerative disease.

Gary: Thank you Ana.

Gary: I'll begin with our ALC is here to program. The most advanced <unk> program in clinical development for Alzheimer's disease.

Gary: <unk> is a novel investigational humanized monoclonal antibody that binds to and activates trend to a key microglia receptor that census, pathological changes in the brain.

Gary: Finding of ALC is here too that the <unk> receptor triggers microbial signaling pathways, which increased microbial proliferation survival and function enhancing the effectiveness of microglia.

Gary: The brand against and salts, including age related neuro degenerative disease.

Gary: We completed our Phase 1 trial of AL002 in healthy volunteers, which demonstrated both dose-dependent target engagement and activation of microglia. In the trial, AL002 was also shown to be well-tolerated. Our ongoing Invoke 2 Phase 2B study of AL002 is a randomized, double-blind, placebo-controlled, common-close design study of up to 96 weeks of treatment with AL002 in which 381 participants with early Alzheimer's were random. The study includes three doses of AL002 that demonstrated robust target engagement and increased microbial signaling in Phase I. InVOTE 2 completed enrollment ahead of schedule in September of last year. The primary clinical outcome measure for this study is the CDR sum of oxygen.

Gary: We completed our phase one trial of <unk> in healthy volunteers, which demonstrated dose dependent target engagement and activation of microglia in the trial Alcs here too was also shown to be well tolerated.

Gary: Our ongoing info two phase <unk> study of <unk> two is a randomized double blind placebo controlled common closed design study.

Gary: We're up to 96 weeks of treatment with <unk>, two in which 381 participants with early Alzheimer's disease were randomized.

Gary: The study includes three doses of <unk> that demonstrated robust target engagement and increased microbial signaling in phase one.

Gary: <unk> completed enrollment ahead of schedule in September of last year.

Gary: The primary clinical outcome measure for the study is the CVR sum of boxes.

Gary: We're also collecting secondary clinical and functional outcome assessments, including V8-SCOG13 and ADCS-ADL-MCI, from which we will derive treatment effects on the Integrated Alzheimer's Rating Scale, or IADR. The trial will also deliver a robust biomarker package reflecting target engagement as well as treatment effects on microglial activity and Alzheimer's pathophysiology. Treatment effects on Alzheimer's pathophysiology will be assessed with CSF and plasma biomarkers of A, beta, and tau, as well as both amyloid and taupet, and we'll also have biomarkers of astrogliosis, neuroinflammation, synaptic health, and neurodegeneration.

Gary: Also collecting secondary clinical and functional outcome assessments, including the Adas Cog 13, Adcs ADL Mci.

Gary: From which we will derive treatment effects on the integrated Alzheimer's rating scale or IHS.

Gary: The trial will also deliver a robust biomarker package, reflecting target engagement as well as treatment effects on microbial activity in Alzheimer's pathophysiology.

Gary: Treatment effects on Alzheimer's pathophysiology will be assessed with CSF plasma biomarkers of a beta and Tau.

Gary: As well as both amyloid and Tau pet and we'll also have biomarkers of Astrogliosis neuro inflammation synaptic health <unk> to generation.

Gary: We intend to use a proportional analysis approach with this study, which will enable us to use all the data collected in this common closed design trial, meaning that it will include data from all participants out to 48 weeks and also include additional, longer-term follow-up from those participants who were in the study for up to 96 weeks. We also have a long-term extension where we'll remain blinded to treatment assignments and thus can provide additional information on long-term safety and also on treatment effects on clinical outcome measures and biomarkers. As we reported last year at AAIC, a subset of participants in the ongoing Invoke 2 trial have had treatment-emergent MRI findings that resemble the amyloid-regated imaging abnormality, or AREA, that has been observed with anti-amyloid therapy. These MRI findings are indistinguishable from ARIA with regard to the MRI features, incidence, timing of onset and resolution, relatedness to the number of ApoE4 alleles, as well as to the frequency and spectrum of associated clinical manifestations.

Gary: Okay.

Gary: We intend to use a proportional analysis approach with the study, which will enable us to use all the data collected in this common close designed trial, meaning that it will include data from all participants out to 48 weeks and also include additional.

Gary: Longer term follow up from those participants who are in this study for up to 96 weeks.

Gary: We also have a long term extension, while we remain blinded to treatment assignment.

Gary: <unk> can provide additional information on long term safety.

Speaker Change: And also on treatment effects on clinical outcome measures and Biomarkers.

Speaker Change: As we reported last year at AIC, a subset of participants and the ongoing into two trial.

Speaker Change: Have had treatment emergent MRI findings that resemble the amyloid related imaging abnormality for area that hasnt been as observed with anti amyloid therapies.

Speaker Change: These MRI findings are indistinguishable from area with regard to the MRI features.

Speaker Change: <unk> timing and of onset and resolution.

Speaker Change: And as to the number of API for Oems as well as to the frequency and spectrum of associated clinical manifestations.

Gary: In the current trial population, that includes ApoE4 heterozygous and ApoE4 non-carrier, analysis of the still-bound data shows an incidence of ARIA-E and ARIA-H of approximately 20%. Of those with ARIA-E, approximately 90% have been asymptomatic, and most symptomatic participants have had mild and self-limited presentations. Most relevant from a clinical perspective, the incidence of clinically serious ARIA, that is, those with ARIA-related SAEs, is just under 1% of all participants that have been diagnosed.

Speaker Change: In the current trial population that includes ethylene for heterozygous in April before non carriers analysis of Theres still blinded data shows an incidence of ARIA E H of approximately 20%.

Speaker Change: Are those with approximately 90% have been asymptomatic and most symptomatic participants who had mild and self limited presentations.

Most relevant from a clinical perspective, the incidence of clinically serious area that is those with area related SAE is is just under 1% of all participants that had been dosed.

Gary: An independent data monitoring committee reviews data from this trial regularly and continues to recommend that the trial proceed. Our goals for the INVOKE-2 trial and for AL002 in the long term are to slow the progression of Alzheimer's disease by therapeutic restoration of microglial function. While one of the potential effects of TRM-2 agonism may be to increase the clearance of misfolded proteins, including amyloid, we expect AL002 to also amplify the broader beneficial effects of healthy microglia in the brain. This includes maintaining synaptic connections, supporting astrocyte and oligodendrocyte function, preserving the blood-brain barrier and vasculature, and Upholding Immune Tolerance.

Speaker Change: An independent data monitoring committee reviews data from this trial regularly and continues to recommend that the trial proceed.

Speaker Change: Our goals for <unk>, II trial and for Alcs here too in the long term or to slow the progression of Alzheimer's disease by therapeutic restoration of microbial function.

Speaker Change: Well one of the potential effects of <unk> agonism.

Speaker Change: Maybe to increase the clearance of Misfolded proteins, including amyloid we.

Speaker Change: We expect <unk> to also amplify the broader beneficial effects of healthy microglia on the brain. This includes maintaining synaptic connections supporting astrocyte milk identify function preserving the blood brain barrier and vascular chair.

Gary: Thus, our expectation is that the restoration of microbial function by AL002 will reduce the brain's vulnerability to neurodegenerative disease 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. Given the multiple mechanisms by which healthy microglia protect the brain against neurodegenerative disease, we hypothesize that by the end of development, AL002 may ultimately display stronger efficacy than current therapies that target individual misfolded proteins. Through its novel and complementary mechanism of action, we expect AL002 to be effective either as a standalone therapy or in combination with anti-amyloid therapy. Given that agonism of TREM2 has the potential to reduce the brain's vulnerability to neurodegenerative disease through these multiple downstream mechanisms, we believe that benefits of AL002 may manifest differently from what we have seen in the anti-amyloid antibody trial. For example, with regard to biomarker responses, lowering the cerebral amyloid PET signal to the 20 to 30 centiloid pressure, 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.

Speaker Change: Upholding immune tolerance.

Speaker Change: Our expectation is is that the restoration of microbial function by ALC is here too we will reduce the brain so on the ability to neurodegenerative disease.

Speaker Change: And at the end of two trial will demonstrate treatment related slowing of Alzheimer's disease progression as demonstrated by a combination of clinical functional and biomarker readouts.

Speaker Change: Given the multiple mechanisms by which healthy microbial protect the brain against Neurodegenerative disease we.

Speaker Change: Hypothesized that by the end of development Alcs here too may ultimately display stronger efficacy at current therapies that target individual misfolded proteins.

Through its novel and complementary mechanism of action, we expect <unk> to be effective either as a standalone therapy.

Speaker Change: In combination with anti amyloid therapies.

Speaker Change: Given that agonism of <unk> two has the potential to reduce the <unk> vulnerability to neurodegenerative disease through these multiple downstream mechanisms. We believe that treatment of benefits of Alcs here too they manifest differently from what we have seen in the anti amyloid antibody trials.

Speaker Change: For example, with regard to biomarker responses lowering cerebral amyloid pet signal to the 20% to 30 satellite threshold, which for anti amyloid antibodies appears to be a necessary condition for clinical efficacy.

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

Gary: 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. And thus, AL002 has potential to benefit patients from preclinical Alzheimer's disease through advanced dementia. I'll now turn to Lada Zinamat, our novel first-in-class progranulone-elevating candidate and the most advanced therapeutic and clinical development for the treatment of frontotemporal dementia. You may recall that laticinimab has previously received both orphan drug designation for FTD and fast-track designation for FTD granulone from FDA. We are pleased to share that in February, FDA granted laticinimab breakthrough therapy designation for STD granulin based on our InFront2 Phase 2 clinical trial data. FDA's breakthrough therapy designation is granted to expedite the development and review of drugs that are intended to treat a serious condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant end point.

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 and our sales years here two has potential to benefit patients from preclinical Alzheimer's.

Speaker Change: Disease through advanced dementia.

Speaker Change: I'll now turn to <unk>, our novel first in class Pro granular and elevating candidate and the most advanced therapeutic in clinical development for the treatment of frontal temporal dementia.

You may recall that latitude as previously received both orphan drug designations Directv and fast track designation for FTE granular from FDA.

Speaker Change: We are pleased to share that in February FDA granted <unk> breakthrough therapy designation for STD granular and based on our in front two phase III clinical trial data.

Speaker Change: Fda's breakthrough therapy designation.

Speaker Change: Granted to expedite the development and review of drugs that are intended to treat a serious condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint.

Speaker Change: With this designation we look forward to continued productive conversations with the FDA recognizing the unmet need for people living with FTE granular in a serious condition for which there are no FDA approved treatment options available.

Gary: With this designation, we look forward to continued productive conversations with the FDA, recognizing the unmet need for people living with FTD granulin, a serious condition for which there are no FDA-approved treatment options available. In October 2023, we achieved target enrollment in the pivotal randomized double blind placebo-controlled phase three clinical trial of laticinimab, randomizing 103 participants with symptomatic FTD granulin and 16 participants who are pre-symptomatic at risk for FTD granulin. Our goal was to enroll 9,200 symptomatic participants, supported by feedback from FDA and EMS. We are actively progressing the INFRNT3 trial in partnership with GSK and look forward to the pivotal phase three data readout following the 96-week treatment period. I'd like to now turn to Ale 101, our second product candidate in our programming portfolio that we are developing in partnership with GSA.

Speaker Change: In October 2023, we achieved target enrollment of the pivotal randomized double blind placebo controlled in front three phase III clinical trial of <unk> randomized in a 103 participants with symptomatic FTE granular 16 participants who are pre symptomatic at risk for FTB granted.

Speaker Change: Our goal is to enroll 90 to 100 symptomatic participants supported by feedback from FDA and EMA.

Speaker Change: We are actively progressing the <unk> trial in partnership with GSK and look forward to the pivotal phase III data readout. Following the 96 week treatment period.

Speaker Change: I'd like to now turn to <unk> 101, our second product candidate and our pro granular portfolio that we are developing in partnership with GSK.

Speaker Change: <unk> <unk> hundred one is a monoclonal antibody that blocks storytelling to elevate per granular levels.

Speaker Change: It's distinct pharmacokinetic and Pharmacodynamic properties have potential to enable dosing regimens that may be more suitable for use in the treatment of larger indications such as Alzheimer's disease.

Speaker Change: Our phase one study in healthy volunteers demonstrated that <unk> hundred one was well tolerated and increased for granular levels in plasma and CSF in a dose dependent manner.

Gary: Like laticinimab, AL-101 is a monoclonal antibody that blocks tortillin to elevate granulone levels. However, distinct pharmacokinetic and pharmacodynamic properties have the potential to enable dosing regimens that may be more suitable for use in the treatment of larger indications such as Alzheimer's. Our Phase 1 study in healthy volunteers demonstrated that AL-101 was well tolerated and increased programmable levels in plasma and CSF in a dose-dependent manner.

Speaker Change: In August 2023 electric GSK received FDA clearance of its IND application for <unk> hundred one in the treatment of early Alzheimer's disease.

Speaker Change: Our rationale for treatment of Alzheimer's disease is that genetic variants that result in modest reduction to pre granular levels are associated with an increased risk of developing Alzheimer's disease.

Speaker Change: Conversely in animal models of Alzheimer's disease elevation of for granular and has been shown to be protected.

Speaker Change: In February of this year, the first participant with dose and the progress study of <unk> hundred one which is being operationalized by our partner GSK.

Gary: In August 2023, Alector and TSK received FDA clearance of its IND application for AL101 in the treatment of early Alzheimer's. The rationale for treating Alzheimer's disease is that genetic variants that result in modest reductions of progranulin levels are associated with an increased risk of developing Alzheimer's. Conversely, in animal models of Alzheimer's disease, elevation of progranulin has been shown to be protective.

Speaker Change: Progress is a randomized double blind placebo controlled phase II clinical trial of <unk> hundred one enrolling approximately 282 patients with early Alzheimer's disease at multiple sites globally.

Speaker Change: The 36 week study is designed to assess the safety and efficacy of two dose levels available in a lung compared to placebo.

Speaker Change: Vince are randomized to one of three dose groups, receiving <unk> hundred one or placebo intravenously.

Gary: In February of this year, the first participant was Ghost in the Progress AD study of AL101, which is being operationalized by our partner GSK. PROGRESS-AD is a randomized, double-blind, placebo-controlled Phase 2 clinical trial of AL-101 enrolling approximately 282 patients with early Alzheimer's disease at multiple sites globally. The 36-week study is designed to assess the safety and efficacy of two dose levels of AL-101 compared to placebo.

Speaker Change: The primary endpoint of the study is disease progression as measured by the <unk> boxes.

Speaker Change: I'll also employs other clinical and functional outcomes assessments and biomarkers.

Speaker Change: We look forward to sharing additional information on our progress.

Speaker Change: As the trial advances.

Speaker Change: With that overview I'll now turn the call over to Sarah to provide an update on our early research pipeline Sara.

Sarah Karimi: Thank you Eddie.

Sarah Karimi: We are making meaningful strides in progressing our research portfolio to fuel our development pipeline and set the stage for our long term growth.

Sarah Karimi: Our drug discovery engine is fine tune through a decade of deep biological exploration.

Sarah Karimi: And expertise in neuroscience as well as strong expertise and experience in antibody protein engineering in preclinical development.

Sarah: Participants are randomized to one of three dose tubes receiving AL-101 or placebo intravenously. The primary endpoint of the study is disease progression as measured by the CDR sum of boxes. The trial also employs other clinical and functional outcomes assessments and biomarkers. We look forward to sharing additional information on PROGRESS-AD as the trial advances. With that overview, I'll now turn the call over to Sarah to provide an update on our Early Research Pipeline. Okay, Sarah?

Sarah Karimi: We have also developed a modular and scalable target discovery platform, which seamlessly integrates genetic multi omics and in house generated wet lab data to uncover novel target.

Sarah Karimi: The system further improve predictions through machine learning based target identification multi dimensional functional validation and data integration with AI based analysis.

Sarah Karimi: Our overall integrated approach allows us to move swiftly from target identification to the development of late stage first in class immuno neurology drug candidates.

Sarah: Thank you, Yeti. We are making meaningful strides in progressing our research portfolio to fuel our development pipeline and set the stage for our long-term growth. Our drug discovery engine is fine-tuned through a decade of deep biological exploration and expertise in neuroscience, as well as strong expertise and experience in antibody, protein engineering, and preclinical development. We have also developed a modular and scalable target discovery platform, which seamlessly integrates genetics, multi-omics, and in-house generated wet lab data to uncover novel targets. The system further improves predictions through machine learning-based target identification, multi-dimensional functional validation, and data integration with AI-based analysis.

Sarah Karimi: In addition to our target and drug discovery engine. We have also made progress on our proprietary Blackburn barrier technology.

Sarah Karimi: While our late stage clinical candidates show brain penetration and target engagement, we are developing a proprietary blood blood brain barrier technology called electro bank caveat, our ABC to strive to lower efficacious doses with favorable safety and efficacy.

Sarah Karimi: Enable delivery of additional novel drugs into the CNS.

We intend to selectively deploy our technology in a fit for purpose manner on a next generation program that are currently in our portfolio.

Sarah Karimi: ABC technologies that toolbox approach incorporating a suite of single chain variable fragment antigen binding pacman are variable heavy chain domains that bind two targets at the black bean value such as Todd said in at <unk> 19, heavy chain with waving affinity.

Sarah: Our overall integrated approach allows us to move swiftly from target identification to the development of late-stage, first-in-class immunoneurology drug candidates. In addition to our target and drug discovery engine, we have also made progress on our proprietary blood-brain barrier. While our late-stage clinical candidates show brain penetration and target engagement, we are developing a proprietary versatile blood vein barrier technology called electrobrain carrier or ABC to strive to lower efficacious doses with favorable safety and efficacy and enable delivery of additional novel drugs into society.

Sarah Karimi: Yes.

Sarah Karimi: We have been able to achieve greater than 10 fold increase in vain concentration multiple cardboard and demonstrated deep brain penetration to sell desktop interest like neuron and microglia.

Sarah Karimi: The modular nature of this technology allows the affinity valency and format of the final therapeutic to be harmonized with the mechanism of action and sell that.

Sarah Karimi: <unk> of the associated cargo.

Sarah Karimi: We are also leveraging our ADC technology to advance the development of protein replacement therapies for neuro degenerative diseases.

Sarah: We intend to selectively deploy our technology in a fit-for-purpose manner on our next-generation programs that are currently in our early portfolio. ABT technology is a toolbox approach incorporating a suite of single-chain variable fragments, antigen-binding fragments, or variable heavy chain domains that bind to targets at the blood-brain barrier, such as transferrin and CD98 heavy chains with varying affinity. We have been able to achieve greater than tenfold increase in brain concentrations of multiple cargos and demonstrated deep brain penetration into cell types of interest like neurons and microbes. The modular nature of this technology allows the affinity, valency, and format of the final therapeutic to be harmonized with the mechanism of action and cell type specificity of the associated cargo. We are also leveraging our ABC technology to advance the development of protein replacement therapies for neurodegenerative diseases, which aligns with our focus on genetic risk factors. Our technology's adaptability is demonstrated through versatile, bite-specific formats, complemented by customizable FC adaptations for optimized effector functions, half-life, and single-chain configuration.

Sarah Karimi: With our focus on genetic risk factors.

Sarah Karimi: Our technologies adaptability is demonstrated through workstyle by specific formats complemented by customizable FC adaptations for optimized effector function half life and single chain configuration.

Sarah Karimi: Based on the translate ability of preclinical safety and efficacy study.

Sarah Karimi: Our technology appears to exhibit a favorable safety profile, even with actively engaging with FSC.

Sarah Karimi: We look forward to sharing more details about our innovative research portfolio, including our electrical brain carrier technology. During a virtual event later this year.

Sarah Karimi: Now turn it over to Mark to provide an update on our financial results Mark.

Mark: Thank you Sarah.

Mark: As summarized in our fourth quarter and full year 2023 financial results, which we made available after the market closed today, we are in a strong cash position to deliver against our strategic objectives.

Mark: We continue to focus on fiscal management and program prioritization and as of December 31, 2023, our cash cash equivalents and short term investments totaled $548 9 million.

Mark: <unk>, our financial position, we completed a follow on financing in January of this year raising $75 million in gross proceeds.

Mark: Based on the translatability of preclinical safety and efficacy studies, our technology appears to exhibit a favorable safety profile even when actively engaging with patients. We look forward to sharing more details about our innovative research portfolio, including our electro-brain carrier technology, during a virtual event later this month. I'll now turn it over to Mark to provide an update on our financial results. Mark?

Mark: Inclusive of this raise our cash runway is now through 2026, approximately a full year beyond the expected ftb's yearend pivotal phase III infront III data readout.

Mark: <unk> two years beyond our time to phase II invoke to data readout.

Mark: Further we are now also in a position to selectively accelerate investment in our innovative proprietary portfolio, including programs enhanced by our proprietary electric brain carrier technology platform.

Mark: Thank you, Sarah. As summarized in our fourth quarter and full year 2023 financial results, which we made available after the market closed today. We are in a strong cash position to deliver against our strategic objective. We continue to focus on fiscal management and program prioritization, and as of December 31, 2023, our cash, cash equivalents, and short-term investments totaled $548.9 million. Strengthening our financial position, we completed a follow-on financing in January of this year, raising $75 million in gross proceeds.

Mark: We appreciate the support of significant new investors as well as participation from our existing shareholders.

Mark: Now turning to our operating results collaboration revenue for the fourth quarter was $15 2 million compared to $14 4 million for the same period in 2022.

Mark: Collaboration revenue for the year was $97 1 million compared to $133 6 million in 2022.

Mark: Total research and development expenses for the fourth quarter were $47 7 million compared to $54 $5 million for the same period in 2022.

Mark: Total research and development expenses for the year were $192 1 million compared to $210 4 million in 2022.

Mark: Inclusive of this raise, our cash runway is now through 2026, approximately a full year beyond the expected FTD-GRN pivotal phase 3, in front 3 data readout, and approximately two years beyond our TREM 2 Phase 2 Invoke 2 data. Further, we are now also in a position to selectively accelerate investment in our innovative proprietary portfolio, including programs enhanced by our proprietary Alector brain carrier technology platform. We appreciate the support of significant new investors, as well as participation from our existing... Now, turning to our operating results, collaboration revenue for the fourth quarter was $15.2 million compared to $14.4 million for the same period in 2022. Collaboration revenue for the year was $97.1 million, compared to $133.6 million in 2022. Total research and development expenses for the fourth quarter were $47.7 million, compared to $54.5 million for the same period in 2022. Total research and development expenses for the year were $192.1 million compared to $210.4 million. Total general and administrative expenses for the quarter were $14.9 million, compared to $15.4 million for the same period in 2022.

Mark: Total general and administrative expenses for the quarter were $14 9 million <unk>.

Mark: Compared to $15 4 million for the same period in 2022.

Mark: Total general and administrative expenses for the year with $56 7 million.

Mark: Baird to $61 million in 2022.

Mark: For 2024, we estimate our collaboration revenue to be between 60% and $70 million.

Mark: Our anticipated total research and development expenses are estimated to be between 210 $230 million.

Mark: Total anticipated general and administrative expenses are estimated to be between 60 and $70 million.

Mark: In December electric close to two virtual research and development events discussing our <unk> and for granular programs in detail the.

Mark: The event included presentations from leading scientific and clinical experts, we encourage those who didn't have an opportunity to participate in the live events to watch. The replay is located under the investor events and presentations section of our website.

Mark: We remain focused on advancing our novel portfolio and electric <unk> technology to treat neurodegenerative diseases.

Mark: We look forward to providing additional updates as we advance our work.

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

Speaker Change: Thank you Andrew.

Speaker Change: As a reminder, if you would like to ask a question. Please press star one on your telephone. Please wait for your name and company to be announced before proceeding with your question one.

One moment, while we compile the Q&A roster.

Speaker Change: Our first question today is coming from Iran.

Speaker Change: We are open to.

Cowen Your line is open.

Speaker Change: Hi, This is brendan on for your own thanks, very much taking the question.

Brendan: Just a couple quick ones from us actually first on the brain carrier program. Just wondering if you might be able to give us a little bit more color on kind of just the broad approach to the platform. I mean, you mentioned transparent and <unk> 98.

Mark: Total general and administrative expenses for the year were $56.7 million compared to $61 million. For 2024, we estimate our collaboration revenue to be between $60 and $70 million. Our anticipated total research and development expenses are estimated to be between $210 and $230 million. In total, anticipated general and administrative expenses are estimated to be between $60-$70. In December, Alector hosted two virtual research and development events discussing our TREM2 and Progranulence programs in detail. The events included presentations from leading scientific and clinical experts. We encourage those who didn't have an opportunity to participate in the live events to watch the replays located under the investor events and presentations section of our website.

Brendan: Are you kind of at this point planning to kind of choose one and use that across the board for all the BC program are you getting any indication.

Brendan: Indication by indication basis.

Brendan: And then I guess really on the ADP <unk> seven asset that you called out in the press release.

Brendan: Kind of just wondering what drove the decision to target GP NMB and maybe how applicable that target would be kind of to the broader market population. Thanks very much.

Speaker Change: Thanks, I'll just address the question about the blood brain barrier technology in the past.

Pass it to <unk> to answer your question on <unk> briefly blood brain barrier approach as we said in place of a versatile vein carrier technology, and we are targeting blood brain barrier proteins, both TFR and CD 19 heavy chain at this moment, we are going up.

Speaker Change: Both these targets and applying them across both our second generation. The second generation efforts for our current late stage programs as well as our new novel sort of target.

Operator: We remain focused on advancing our novel portfolio in electrobrain care technology to treat neurodegenerative diseases. We look forward to providing additional updates as we advance our work. That concludes our prepared comments for today's call. Operator, you may now open the line.

Speaker Change: Molecules in research.

Speaker Change: And certainly do not have any intent initially to choose one or the other we will depending on the best the best approach for each target in each molecule.

Speaker Change: Again, we are using very adaptable technology, which allows us to customize but therapeutic affinity valency et cetera, we've got bi specific formats and customizable FTE adaptations that allow us to.

Operator: Thank you. As a reminder, if you would like to ask a question, please press star 11 on your telephone. Please wait for your name and company to be announced before proceeding with your question.

Operator: One moment while we compile the Q&A roster. Our first question today is coming from Yaron. Worben of TD Cal will answer when your line is open.

Speaker Change: Tweak effector function as well as optimize half life on the molecule. So it's our approach currently is too.

Speaker Change: Tried both these both these approaches targeting approaches Tropicana approaches both for our late stage programs as well as for our novel targets.

Brendan: Hi, this is Brendan on for your own. Thanks very much for taking the questions. We have just a couple quick ones from us. Actually, first on the Brain Carrier Program. Just wondering if you might be able to give us a little bit more color on kind of just the broad approach to the platform. I mean, you mentioned Transparent and CD98.

Speaker Change: Maybe Ireland can share his thoughts on our ADP or to seven program that chicken.

Ireland: Yes, so yes, we do think that <unk>.

Ireland: Targeting will be applicable for sporadic Parkinson's disease GP RMB.

Ireland: Lysosomal regulate.

Ireland: So Jim for Parkinson's disease, both risk and protective barriers and we developed a drug that maybe you can exceed the protective <unk>, we think that.

Sarah: Are you kind of at this point planning to kind of choose one and use that across the board for all the BC programs, or are you going to go indication by indication? And then, really, on the ADP-027 asset that you called out in the press release. I'm kind of just wondering what drove the decision to target GPNMB and maybe how applicable that target would be to the broader Parkinson's population. Thanks.

Ireland: Okay.

Ireland: Yes.

Ireland: Pathology, Jeremy will feature in Parkinson's disease.

J: J P I might be.

Speaker Change: <unk> we've interrupting.

Speaker Change: Two other this June for Parkinson's disease.

Speaker Change: Regulated in multiple types of sporadic PBS so we do think that.

Speaker Change: Will be applicable for any type of Parkinson's disease.

Speaker Change: Alright, thanks very much.

Speaker Change: Thank you one moment for the next question.

Sarah: I'll just address the question about the blood-brain barrier technology, and then I'll pass it to Arnon to answer your question about GPNMB. Briefly, you know, our blood-brain barrier approach, as we said, employs a very versatile brain carrier technology, and we are targeting blood-brain barrier proteins, both TFR and CD98 heavy chain. At this moment, we are going after both these targets and applying them across both our second-generation efforts for our current late-stage programs, as well as our new, novel sort of target molecules in research, and certainly do not, you know, have any intent initially to choose one over the other. We will, depending on the best approach for each target and each molecule. Again, we are using, you know, very adaptable technology which allows us to customize for therapeutic affinity, valency, etc. We've got bi-specific formats and customizable FCA adaptations that allow us to tweak effective function as well as optimize half-life on the molecule.

Speaker Change: And our next questioner today will be coming from Paul Mcginnis.

Speaker Change: Paul.

Hi, This is Julian entre Paul Thanks, so much for taking our question I.

Paul Mcginnis: I guess on Al zero zero to the <unk> two program.

Paul Mcginnis: With the readout expected towards the end of the year the trials.

Paul Mcginnis: Anticipated to run for about a year at least for at least at a minimum in terms of follow up I guess, what gives you guys confidence that this will be a long enough to separate from placebo.

Paul Mcginnis: And do you anticipate at all that there will be a significant group of patients out to two years.

Paul Mcginnis: And any other color on how the overall data will be analyzed our shared in our top line would be super helpful. Thank you.

Paul Mcginnis: Yes, hi, Thanks for the question this is Gary.

Gary: So the study as you heard was a common close decide in which.

Gary: All patients will stay in the trial for up to 96 weeks.

Gary: And then rollover into a long term extension and that is until the last patient out.

Reaches 48 weeks at which time all patients will rollover into the long term extension.

Gary: And so we will have data not only where we have data out to 48 weeks on everybody, but we'll also have <unk>.

Gary: Data out to two we will have for example, critical outcome assessments out to 96 weeks.

Arnon: So our approach currently is to, you know, try both these approaches, targeting approaches, and trafficking approaches, both for our late-stage programs as well as for our novelty. Maybe Arnon can share his thoughts on our ADP 027 program. Yes. So yeah, we do think that GPNMB targeting will be applicable for sporadic Parkinson's disease. GPRNB is a lysosomal regulator.

Gary: On a good subset of patients.

Gary: We're planning to use and analysis method called the proportional analysis method or proportional MRM for example, which uses all of the data. So it's not just the time to event at one time point, but.

Gary: It includes data at all from all time points. So it's a way of getting the most out of your data by.

Arnon: It's a risk gene for Parkinson's disease. There are both risk and protective variants, and we developed a drug that mainly can exceed the protective variants. And we think that sort of

Gary: By using all of the data in.

Gary: That's our plan for the analysis for the primary analysis.

Gary: You asked the question about do we think this is enough time to see treatment effect.

Arnon: Lysosomal pathology is a general feature in Parkinson's disease, and GPMMB is interacting with LRRK2, and is interacting with GCAS, two other risk genes for Parkinson's disease. It's upregulated in multiple types of sporadic PD, so we do think that it will be applicable to any type of Parkinson's disease. All right, thanks very much. Thank you. One moment for the next question. And our next question today will be from Paul Mathias of SIPHON. Hi, this is Julian Antropol.

Gary: We're looking at treatment effect in this study.

Abbvie.

<unk> designed the study in order to be a biomarker rich study.

Gary: We'll look at the totality of the data so looking to see that we can slow Alzheimer's disease through a combination of clinical functional and biomarker readouts.

Gary: And we're going to have a very robust biomarker package that includes not only what we originally intended which would be <unk>.

Gary: Immolated Tau pet sub studies, but also now with the.

Gary: Thanks so much for taking our question. I guess on AL002, the TRM-2 program, with the readout expected towards the end of the year, the trials are expected to run for about a year, at least for at least at least in terms of follow up. I guess what gives you guys confidence that this will be long enough, separate from placebo, and do you anticipate at all that there will be a significant group of patients out to two years? Any other color on how the overall data will be analyzed or shared in a top line would be super helpful. Thank you. Hi, thanks for the question. This is Gary.

Gary: The acceleration.

Gary: And validation.

Gary: Foster Tau assays will be looking at pizza on seven and Tau aggregates in plasma on all patients. So we feel confident that we're going to through this totality of this data will be able to determine whether we are slowing the progression of Alzheimer's disease, which is what the individual design was intended to do.

Speaker Change: Excellent thanks for the color.

Speaker Change: Thank you one moment for the next question.

Jeff Hung: And our next question will be coming from Jeffrey hung.

Jeff Hung: Of Morgan Stanley Your line is open.

Speaker Change: Hi, Hi, this is Michael on for Jeff hung. Thank you for taking my question.

Gary: So, the study, as you heard, is a common-close design in which all patients will stay in the trial for up to 96 weeks and then roll over into long-term extension, that is, until the last patient out reaches 48 weeks, at which time all patients will roll over into long-term extension. And so, we will have data; not only will we have data after 48 weeks on everybody, but we'll also have data out. We'll have, for example, clinical outcome assessments out to 96 weeks on a good subset of patients. We're planning to use an analysis method called a; it's a proportional analysis method or proportional MMRM, for example, which uses all of the data.

Speaker Change: For invoke how do you expect levels of soluble <unk> silicon for patients at baseline was preclinical I D versus maybe a little bit more progressed dementia like does the higher baseline soluble tend to level like imply higher chances for like a pharmacodynamic effect.

Speaker Change: So first let me just this is Gerry again.

Gerry: To clarify we are enrolling patients as you said with early Alzheimer's disease, we are not.

Gerry: Rowling enrolling for example, just those with genetic variance.

Gerry: Like the <unk> 77 H variant.

Speaker Change: We don't believe that.

Speaker Change: Baseline levels of soluble <unk> necessarily we don't really know whether thats going to predict a pharmacological effect, but what we would expect in our study.

Gary: So it's not just a time to event at one time point, but it includes data from all time points. So it's a way of getting the most out of your data by using all of the data and that's our plan for the analysis, for the primary analysis. You asked a question about whether we think this is enough time to see a treatment effect. You know, we're looking at treatment effect in this study as Abhi and Alector designed the study in order to be a biomarker-rich study that will look at the totality of the data. So we're looking to see that we can slow Alzheimer's disease through a combination of clinical, functional, and biomarker readouts. And we're going to have a very robust biomarker package that includes not only what we originally intended, which would be amyloid and tau PET substudies, but also now with the acceleration and validation of phospho-tau assays. We'll be looking at P217 and tau aggregates in plasma on all of them. So we feel confident that through this totality of this data, we are going to be able to determine whether we're slowing the progression of Alzheimer's disease, which is what the original design was intended. Thanks for the call.

Speaker Change: Is that.

Speaker Change: The binding of the Av.

Speaker Change: ALC is here too <unk> two causes internalization of the receptor and this actually causes a.

Speaker Change: Reduction insoluble trend too because like we're basically doing is is reducing by binding and internalizing receptor, we're lowering the levels of microbial membrane trend to which.

Speaker Change: And that reduces the amount of the cleavage products valuable attempt to which is consistently cleaved.

Speaker Change: Or.

Speaker Change: And.

Speaker Change: Right. So so we plant we will see as we saw we intend to see as we did in phase one a reduction in cycle time too.

Speaker Change: Again, theres different ideas about soluble tend to with what it's always we believe that primarily.

Really a marker of membrane trend too.

Speaker Change: And.

Speaker Change: And.

Speaker Change: There have been Theres, a fair amount of data out there that suggests that.

Speaker Change: <unk> levels, which are again are reflecting the amount of churn in the membrane correlate as they are higher than they correlate with with better outcomes or progression of disease.

Gary: Thank you. One moment for the next question. And our next question will be coming from Jeffrey Hung of Morgan Stanley. Your line is open. Hi, this is Michael Riad on behalf of Jeff Hung.

Speaker Change: Of Alzheimer's disease or slower.

Speaker Change: Conversion from Mci to Alzheimer's disease.

Speaker Change: Slower progression of brain volume loss.

Michael Riad: Thank you for taking our question. For Invoke, how do you expect levels of soluble TREM-2 to look for patients at baseline with preclinical AD versus maybe a little bit more advanced dementia? For example, does a higher baseline soluble TREM-2 level like imply higher chances for like a pharmacodynamic effect?

Speaker Change: So again, but that is a function basically of having greater trend to activity in our antibody.

Speaker Change: As a increases chunk to signaling.

Speaker Change: Thank you so much really helpful.

Yes.

Speaker Change: Thank you one moment to the next question.

Speaker Change: And our next question will be coming from Pete Stavropoulos of Cantor Fitzgerald. Your line is open.

Gary: So, first, let me just, this is Gary again, just to clarify. We are enrolling patients, as you said, with early Alzheimer's disease. We're not enrolling, for example, just those with genetic variants like the R477H variant. You know, we don't believe that the baseline levels of soluble CHEM-2 necessarily, we don't really know whether that's going to predict a pharmacological effect, but what we would expect in our study is that the binding of AL002 to CHEM-2 causes internalization of the receptor. And this actually causes a reduction in soluble CHEM-2 because what we're basically doing is reducing, by binding and internalizing the receptor, we're lowering the levels of microglial membrane CHEM-2, which, and that reduces the amount of the cleavage product, soluble CHEM-2, which is constitutively cleaved from CHEM-2, right?

Pete Stavropoulos: IR team. Thank you for taking my questions.

Pete Stavropoulos: So first one I believe that for the invoke to study the placebo rolls over you'll start you'll be starting at a lower dose than those in the original randomized to active arm and then Ty trading them upwards.

Pete Stavropoulos: Can you just discuss the timeline for the titration and will you be able to capture any data points, especially biomarker wise.

Pete Stavropoulos: Would suggest that the starting doses therapeutically active and if so what would be the key biomarker of Biomarkers are you believe maybe informative at that time point.

Pete Stavropoulos: Okay.

Speaker Change: Yes, Thanks Keith.

Speaker Change: Question.

Speaker Change: So you are right we are so.

Speaker Change: Just to clarify in the long term extension all patients that were on active.

Gary: So we plan, we will see, as we saw, and we intend to see, as we did in phase one, a reduction in soluble CHEM-2. Again, there are different ideas about soluble TREM2 and what its role is, but we believe that primarily it's really a marker of membrane TREM2.

Speaker Change: Doses in the double blind will rollover to the same dose and continue in the long term extension.

Speaker Change: Those that were originally randomized to placebo will.

Speaker Change: <unk> rolled out the titrated up.

Speaker Change: Started on active beginning with a tight with a at a lower dose that's right six milligrams per kilogram and.

Gary: And and, you know, there's a fair amount of data out there that suggests that siloful TREM2 levels, which are again, reflecting the amount of TREM2 in the membrane, correlate, you know, as they are higher, they correlate with better outcomes or progression of disease in Alzheimer's disease, slower conversion from MCI to Alzheimer's disease, and slower progression of brain volume loss. So again, but that is a function basically of having greater TREM2 activity, and our antibody is an increase in TREM2 signal. Thank you so much.

Speaker Change: And increase and they will they will have been dose escalated every two months.

Speaker Change: And <unk>.

Speaker Change: One reason for doing this is to learn more about the potential mitigation for the area like signal that we're seeing.

Speaker Change: Some of the anti amyloid therapeutics has been.

Speaker Change: So data that suggests that starting at a lower dose <unk> tight trading more slowly.

Speaker Change: And then we did in this double blind study could be mitigated. So that's one advantage. We do believe that this slow titration that was actually going to help us in another way not only to learn about mitigation for area, but also help us too.

Gary: Really helpful. Thank you. One moment for the next question, and our next question will be coming from Pete Stavropoulos of Cantor Fitzgerald. Your line is open.

Keith: Thank you for taking my questions. So, first one, I believe that, for the Invoke 2 study, the placebo rolls over. You will start, you know, you will be starting them at a lower dose than those in the original randomized active arm and then, you know, titrating them upwards. Can you just, you know, discuss the timeline for the titration? And will you be able to capture any data points, you know, especially biomarker-wise, that could suggest that the starting dose is therapeutically active? And if so, what would be the key biomarker or biomarkers you believe may be informative at that time? Yeah, thanks, Keith. That's a good question.

Speaker Change: In a sense it will.

Speaker Change: Long term extension, which by the way, we invested with Abbvie to keep this blinded to the original treatment assignment. This will give us an opportunity to continue to follow patients beyond the double blind into the long term extension.

Speaker Change: To us to look for not only for safety, but also to look for treatment effects on Biomarkers and most importantly on clinical outcome measures. So before for example.

Speaker Change: With the common close design some of the patients will have a near only a year.

Speaker Change: Data follow up data on clinical outcomes, but in the long term extension, which would really.

Gary: So, you're right; we are so. Just to clarify, in the long-term extension, all patients that were on active doses in the double blind will roll over to the same dose and continue in the long-term extension. Those that were originally randomized to placebo will now be titrated, started on active, beginning at a lower dose, that's right, six milligrams per kilogram, and they will be dose escalated every two months, and one reason for doing this is to learn more about the potential mitigations for the area-like signal that we're seeing, as you know, and some of the anti-amyloid therapeutics have data that suggests that starting So that's one advantage.

Essentially would be a randomized start design will be able to look forward.

Speaker Change: Differences between the original placebo group and Andy.

Speaker Change: Active dose groups.

Speaker Change: In the long term extension, we will be able to look at those clinical outcome assessments and differences from the UK to placebo and active.

Speaker Change: <unk> long term extension.

Speaker Change: Alright, thank you for that.

Speaker Change: One question on the on the Phase III for Al 101.

Speaker Change: We recently initiated with GSK.

Speaker Change: Looking at the study design I see that there are two undisclosed doses being evaluated.

Speaker Change: How did you select those doses if you can tell us I know it was it based on a certain level of.

Speaker Change: Prs <unk> increase in the phase one are you trying to keep it above a certain threshold or below a certain level.

Speaker Change: Sarah I'll start maybe Sarah if you want to chime in on on the PK here.

Gary: We do believe that this slow titration is actually gonna help us in another way, and not only to learn about mitigation for ARIA but also to help us to, in a sense, it will help us with this long-term extension, which, by the way, we invested with AbbVie to keep this blinded to the original treatment assignment. This will give us an opportunity to continue to follow patients beyond the double-blind into the long-term extension to look for not only safety but also treatment effects on biomarkers and, most importantly, clinical outcomes. So, you know, for example, with the common closed design.

Speaker Change: Hi.

Sarah Karimi: Yes, so we have two doses we have eight.

Sarah Karimi: Well a maximal dose.

Sarah Karimi: Us maximal.

Sarah Karimi: Elevations of pro granular.

Sarah Karimi: And we also chose <unk>.

Sarah Karimi: Lower dose.

Sarah Karimi: And those the.

Sarah Karimi: Im not sure how much of this we've disclosed in terms of the actual doses and the.

Sarah Karimi: The randomization ratios, so I'm going to have to.

Sarah Karimi: <unk> market share as to whether where we are.

Sarah Karimi: Yes.

Sarah Karimi: Okay.

Speaker Change: Thanks, Gary agreed piece, we haven't disclosed the actual doses are the collection, but mostly.

Gary: Some of the patients will have a year of data, follow-up data on clinical outcomes, but in the long-term extension, which would really... Thank you, be able to look at those clinical outcome assessments and differences from the placebo inactives over that long-term. Thank you for that. And you know, one question on phase two for AL-101, originally initiated with GSK, you know, just, um, you know, looking at the study design, I see that there are two undisclosed doses being evaluated. You know, how did you select those doses? You know, if you could tell us, was it based on a certain level of, you know, PRG, PG, PRG increase in phase one? And, you know, are you trying to keep it above a certain threshold or below a certain level? Sorry, I'll start.

Speaker Change: The doses are selected based on the PK and PD data that was generated in our phase one single and multiple ascending dose study and based on program and endeavors of course. So it was the elevation of program alone in plasma and CSF that was modeled and based on this the two doses selected we haven't.

Speaker Change: The really shared the exact doses are the exact criteria for the selection of the dose.

Speaker Change: Okay. Thank you for taking my questions.

Speaker Change: Thank you one moment for the next question.

Speaker Change: The next question will be coming from Greg Harrison of Bank of America. Your line is open.

Hey, good afternoon, thanks for taking the question.

Greg Harrison: What endpoint.

Greg Harrison: He will report from the book to trial.

Greg Harrison: Do you think will be key to understanding the benefit of.

Greg Harrison: Hello to various mechanisms beyond amyloid reduction and potentially shine differentiation versus anti amyloid antibodies.

Sarah: Maybe, Sarah, if you want to chime in on the PK here behind it. Yeah, so we have two doses. We have a maximal dose that gives us maximal elevations of progranulin, and we also chose a lower dose.

Speaker Change: Yes. Thank you for that question Greg.

Speaker Change: So just to remind everyone.

Speaker Change: The mechanism here is that we believe is therapy therapeutic restoration of microglia function that.

Sarah: I'm not sure how much of this we've disclosed in terms of the actual doses and the randomization ratio, so I'm going to have to defer to Mark or Sarah as to whether we're, we are. That's all you've got at this time. Thanks, Gary. Agreed, Pete. We haven't disclosed their actual doses or the selection, but mostly that the doses were selected based on the PK and PD data that were generated in our phase one single and multiple ascending dose studies and based on progranulin levels, of course. So it was the elevation of progranulin in plasma and CSF that was modeled, and based on this, the two doses were selected.

Speaker Change: That will slow disease progression and as you mentioned that includes.

Speaker Change: May include enhanced clearance of Misfolded proteins like amyloid, which we know is one of the important function of microglia.

Speaker Change: There were also a number of other beneficial effects of microglia.

Speaker Change: That they do.

Speaker Change: Normal maintenance to preserve brand health reduce vulnerability of the brain to insult.

Speaker Change: Insults, including age related hearing degenerative diseases.

Speaker Change: And I think we mentioned there's a couple of times in the presentation.

Speaker Change: So.

Speaker Change: The.

Sarah: We haven't really shared the exact doses or the exact criteria for the, Okay, thank you for taking my question. Thank you. One moment for the next question. The next question will be coming from Greg Harrison of Bank of America. Your line is open. Hey, good afternoon.

Speaker Change: In this study therefore, we are.

Speaker Change: And then again this is a novel mechanism and we think that it's important too to.

Speaker Change: Realize that.

Speaker Change: <unk>.

Speaker Change: That through these various.

Speaker Change: Downstream mechanisms are healthy.

Speaker Change: Healthy.

Greg: Thanks for taking the question. What endpoints that you'll report from the Invoke-2 trial do you think will be key to understanding the benefit of ALO2's various mechanisms beyond amyloid reduction and potentially showing differentiation versus anti-amyloid antibodies? Yeah, thank you for that question, Greg. So, you know, just to remind everyone, the mechanism here is that we believe is therapeutic restoration of microglial function that will slow disease progression. And as you mentioned, that may include enhanced clearance of misfolded proteins like amyloid, which we know is one of the important functions of microglia, but there are also a number of other beneficial effects of microglia that they do in normal maintenance to preserve brain health and reduce vulnerability of the brain to insults, including age-related neurodegenerative diseases, and I think we mentioned those a couple of times in the presentation.

Speaker Change: Play because of the healthy microglia.

Speaker Change: Yes.

Speaker Change: Sure.

Speaker Change: There are a number of things we can measure and we're going to be measuring in the study including outside the typical alpine respond markers. So we mentioned a beta and tau both in plasma.

Speaker Change: Pet scans.

Speaker Change: We will also be measuring.

Speaker Change: Astrocytes.

Speaker Change: Exxon astrocytes and synapses.

Speaker Change: Oh go dentistry function et cetera.

Speaker Change: I think the totality really well.

Speaker Change: But the decision is going to be based on though is whether or not we're slowing the progression of Alzheimer's disease, and so all of those mechanisms.

Speaker Change: To be meaningful has to add up to a slowing in the progression of disease and that will probably be best measured.

Speaker Change: By clinical outcome measures and also by Biomarkers.

Gary: So, in this study, therefore, we are, and again, this is a novel mechanism, and we think that it's important to realize that through these various downstream mechanisms that are in play because of healthy microglia, there are a number of things we can measure, and we're going to be measuring in the study, including outside the typical Alzheimer's biomarkers that we mentioned, the beta and tau, both in plasma and on PET scans. We'll also be measuring astrocytes, you know, effects on astrocytes and synapses and oligodendrocyte function, etc. I think the totality, really what the decision is going to be based on, though, is whether or not we're slowing the progression of Alzheimer's. And so all of those mechanisms, if... to be meaningful, have to add up to a slowing in the progression of disease, and that will probably be best measured by clinical outcome measures and also by biomarkers. And of those biomarkers, not only A-beta but, very importantly, the tau biomarkers. Because we know that tau, changes in tau, and tau aggregates travel or, you know, correlate most closely with disease progression in NAD.

Speaker Change: Those biomarkers not only a beta but very importantly, the tau biomarkers, because we know the tau changes in talent aggregates.

Speaker Change: Travel.

Speaker Change: Correlate most closely.

Speaker Change: With disease progression.

Speaker Change: And so we will be looking at clinical outcome measures will be looking at the Alzheimer's Biomarkers, particularly for example, plasma pizza on southern and also looking at how aggregates with other.

Speaker Change: Other tau fossil assays.

Speaker Change: Microtubule binding region assay.

Speaker Change: Want to emphasize.

Speaker Change: The study is powered for.

Speaker Change: For clinical effects of about 40%, that's a big effect. So we.

Speaker Change: We may or we may not see a clinically significant effect size in this relatively small phase II study.

But again the original design was intended.

Speaker Change: Not to not to be to.

Speaker Change: B have a decision made on the primary clinical endpoint, but on the totality of the data, particularly.

Speaker Change: The biomarker data that I mentioned.

Speaker Change: Got it that's really helpful. Thanks.

Speaker Change: Thank you thanks Craig.

Speaker Change: One moment and our next question will be coming from Corinne Johnson.

Gary: And so we'll be looking at the clinical outcome measures. We'll be looking at the Alzheimer's biomarkers, particularly, for example, plasma P217, and also looking at tau aggregates with other tau phosphoassays, like the microcephalobinding region assay. I want to emphasize that the study is powered for a clinical effect of about 40%. That's a big effect.

Corinne Johnson: I'm Goldman Sachs. Your line is open.

Corinne Johnson: Hi, This is clinical and forgive me, just Glenn who knows.

Corinne Johnson: Could you please share what's embedded in the cash G&A guidance with respect to clinical activities.

Corinne Johnson: Under new identity Macinnis, Inc.

Corinne Johnson: Yes. Thanks for the questions I think the question was around what what's included in the cash runway guidance. So.

Speaker Change: The cash runway guidance as noted.

Speaker Change: Now through 2026.

Speaker Change: Yes.

Speaker Change: Two years post the anticipated <unk> two data and also approximately a full year beyond the anticipated at.

Gary: So, you know, we may or we may not see a clinically significant effect of that size in this relatively small phase two study. But again, the original design was intended not to have a decision made on the primary clinical endpoint but on the totality of the data, particularly the biomarker data that I mentioned.

Speaker Change: <unk> phase III data and also allows us to accelerate.

Speaker Change: Our investment in our blood brain barrier technology platform and also.

Speaker Change: Earlier stage pipeline.

Speaker Change: Importantly.

Speaker Change: Yes.

Speaker Change: As conservative in the sense that we're not including any milestones for partners, including the potential significant opt in from Abbvie.

Gary: That's, that's really helpful. Thanks. Thank you. One moment. And our next question will be coming from Corinne Johnson, of Goldman Sachs. Your line is open. Hi, this is Palak on for current just one for us.

Speaker Change: And.

Speaker Change: The completion of the phase III.

Speaker Change: And it does include a full spend on <unk> through.

Palak: Can you please share what's embedded in the cash runway guidance with respect to clinical activities more so beyond the near-term clinical event? Yeah, thanks for the question. I think the question was around what's included in the cash runway guidance.

Speaker Change: The phase III completion also continued spend on that program for the extension study.

Speaker Change: And <unk>.

Speaker Change: Spend on the FTE at each year and phase III and also spend on the recently commenced.

Speaker Change: Dale.

Speaker Change: Zero, one phase II for all Samaras disease. Those are the major components. In addition to.

Mark: So the cash runway guidance, as noted, is now through 2026, two years post the anticipated TRMM2 data and also approximately a full year beyond the anticipated FTD-GRN phase 3 data and also allows us to accelerate our investment in our blood-brain barrier technology platform and also, potential significant opt-in from AbbVie at the end of the completion of the Phase 2, and it does include a full spend on 002 through the Phase 2 completion Those are the major components in addition to... you know, continuing to progress our... Understood, thank you. Thank you. One moment for the next question. And our next question is coming from Carter Gould of Barclays. Your line is open. This is Leon Ong for Carter.

Speaker Change: Continuing to progress our.

Speaker Change: Blood brain barrier platform, an early pipeline.

Speaker Change: Yeah.

Speaker Change: Understood. Thank you.

Speaker Change: Thanks for the question.

Speaker Change: Thank you one moment for the next question.

Speaker Change: And our next question is coming from Carter Gould.

Carter Gould: Barclays. Your line is open.

Carter Gould: Hi, This is Leon on for Carter. Thanks for taking my question. So we have two on invoke <unk>.

Leon: So at this point do you have alignment or understanding with abbvie on what a potentially good <unk>.

Profile could look like.

Speaker Change: On the readout.

And in terms of your update on achieving 90% enrollment in the Oi from it and vocal to now that's against the backdrop.

Speaker Change: Having the RVO like effects you've seen.

Speaker Change: So we wanted to get your thoughts here on the implication of getting.

Leon Ong: Thanks for taking my question. So, we have two on Invoke02. So at this point, do you have alignment or understanding with AbbVie on what a potentially good profile could look like on the readout? And in terms of your update on achieving 90% enrollment in the OLE from Invoke02, now that's against the backdrop of having the ARIA-like effects you've seen. So, we want to get your thoughts here on the implications of, you know, getting 90% enrollment in the OLE.

Speaker Change: Sure.

Speaker Change: 90% enrollment in the oil is there some nuance that we're missing or anything that you'd like to highlight in terms of what this could tell you about the safety and Tolerability profile. Thank you.

Speaker Change: Yes, well to the latter question.

Speaker Change: Just that 90% of those those that were eligible to roll over out of the.

Speaker Change: Out of the 90 60 common close designed study.

Speaker Change: And.

Speaker Change: And I.

Speaker Change: I think that we believe that reflects.

Gary: Is there some nuance that we're missing or anything that you'd like to highlight in terms of what this could tell you about the safety and tolerability profile? Thank you. Yeah, well, to the latter question, just that that's 90% of those that were eligible to roll over out of the 1960s common clothes design study and, and, you know, I think that it reflects an interest in patients to continue, there are increasingly other options like they can, to start taking Leucanomab. But most, if you hear, 90% or so are rolling over and staying in the long-term extension, which we interpret positively in terms of tolerability and potentially, you know, other effects of the drug, but we can't, we really can't.

Speaker Change: And interest in patients to continue there are increasingly other other options like they could start taking autonomy.

Speaker Change: But most.

Speaker Change: Hiro.

Speaker Change: 90% or so or are rolling over and staying in which in the long term extension, which we.

Speaker Change: Interpret positively in terms of Tolerability and potentially.

Speaker Change: Other effects of the drug where we can't really can't.

Speaker Change: No.

Speaker Change: Speculate on at this point.

Speaker Change: I'm blanking on your first question I'm sorry.

Can you just remind me the beginning im sure ill remember youre, asking you're asking why not remember now about the readout right. So.

Speaker Change: Alright, sorry, I, just blanked out there so yes, so as I mentioned.

Gary: I speculate on. I'm blanking on your first question. I'm sorry. Can you just remind me in the beginning? I'm sure I'll remember it.

Speaker Change: We've been aligned with Abbvie really from the start on and how we design the study.

Speaker Change: That that we're really looking at the totality of the data to tell us whether we're slowing the progression of Alzheimer's disease, which would which to make a decision.

Gary: You're asking, you're asking. Oh, I know. I remember now about the readout. Right. So, yeah. So, I'm sorry. I'm sorry.

Gary: I just had a blank out there. So, yeah. So, as I mentioned, we've been aligned with AbbVie really from the start on how we designed this study, you know, that we're really looking at the totality of the data to tell us whether we're slowing the progression of Alzheimer's disease, which would, you know, make a decision on what happens next with this compound and whether it progresses. So that includes, you know, that includes, as I said And it includes some functional measures, and it includes a lot of biomarkers.

Speaker Change: What happens next with this compound and whether it progresses. So that includes that includes as I said clinical our clinical outcome measures.

Speaker Change: It includes some functional measures and it includes a lot of Biomarkers.

Speaker Change: So and particularly we're thinking that we'll be really focusing on those Alzheimer's biomarker. It's about sign responses geology to tell us that we are seeing some slowing of disease progression.

Speaker Change: Got it. Thank you answered your question yes.

Speaker Change: Thank you one moment for the next question.

And our next question will be coming from Myles Minter William Blair. Your line is open.

Gary: So and particularly, you know, we're thinking that we'll be really focusing on those Alzheimer's biomarkers of Alzheimer's pathophysiology to tell us that we are seeing some slowing of the disease. Roger, thank you. Thank you. One moment for the next question. And our next question will be coming from our mentor, William Blair. Your line is open. Hi, just a couple on Invoke 2.

Myles Minter: Hi, just a couple on <unk>.

Myles Minter: And then any sort of material differences that youll, saying and the ARIA incidence rates between the double blind portion of impact to the long term open label extension I would assume that are you guys stopped if youre, having placebo switch to active drug in that.

Gary: Are there any sort of material differences that you're seeing in the ARIA incidence rates between the double-blind portion of Invoke 2 and the long-term open label extension? I would assume that ARIA goes up if you're having placebo switch to active drug in that arm. That's the first question. The second one is whether you're measuring tau in all of those patients. Are you going to do a primary analysis by which you stratify by tau burden similar to what Eli Lilly did and others have done in a post hoc setting? Thanks. Yeah, thank you. The second question, we will have the capability of doing that post-hoc, you know, we didn't stratify the study based on tau, but we will be able to look with plasma p-tau measures in order to see whether there are differential effects based on baseline tau, not just baseline tau, and I should do this in the other direction. And your first question was, oh, about the ARIA signal. Yeah, so.

Myles Minter: The first question. The second one is you mentioned the Tau and all of those patients.

Myles Minter: You're going to do a primary analysis by which you stratify by Talbert and similar to what <unk> literally did and others have done in a post hoc setting. Thanks.

Speaker Change: Yes. Thank you and the second question, we will we will have the capability of doing that post.

Speaker Change: We didn't we didn't we didn't stratify the patient.

Speaker Change: The study based on power, but we will be able to look with positive plasma pizza.

Speaker Change: Pat.

Measures in order to.

Speaker Change: In order to see whether there are differential effects based on baseline tell tell off not the baseline how apathy yep.

Speaker Change: And.

Speaker Change: I guess you didn't see any of the other direction and your first the first question was Oh around.

Speaker Change: The area of signal yet so.

Gary: We've shown, we've shared this data, the imaging, the MRIs, the MRIs themselves, the clinical vignettes of these patients. And truly, this looks indistinguishable from the area that has been described with anti-amyloid antibodies in every regard, with regard to its timing of onset. For example, we see this early in treatment, and then it really tapers off the time to onset and resolution, the reactivity to number of A2E4 alleles, the MRI features themselves, and the clinical manifestation. So we don't see any differences, and we've shown it to a number of ARIA experts who have also said that this is really indistinguishable.

Speaker Change: We've shown we've shared this data imaging.

Speaker Change: The MRI.

Speaker Change: The MRI themselves the clinical vignettes. These patients truly this looks indistinguishable from the area that has been described with anti amyloid antibodies.

Speaker Change: In every regard with regard to its timing of onset for example, we see this early in treatment and then it really tapers off.

Speaker Change: The the time.

Speaker Change: Time to onset and resolution.

Speaker Change: It will be related to April two number right so before wheels MRI.

Speaker Change: The MRI features themselves and the clinical manifestations, so it really really well.

Speaker Change: I don't see any differences and we've shown it to a number of.

Speaker Change: The area experts, who have also said that this is and it really indistinguishable.

Gary: And I don't think we see any difference between the main study and the extension study either. Okay, so no difference from the 19 or 23 percent that you reported at AANIC compared to your most recent... Yeah, no, sorry. Sorry. We, you know, we're blinded to who's who in the study. But, you know, so far, so far, we have seen very little area in the long term, earlier days with the extensional study miles, so, you know, to try to draw inferences from those percentages.

Speaker Change: And I don't think we see any differences between the main study and the extension study there Myles to your.

Speaker Change: Question, Okay sorry.

Speaker Change: Sorry.

Speaker Change: From the non China, 23% that you reported.

Speaker Change: Yes.

Speaker Change: Yes, no sorry, sorry.

Speaker Change: Were blinded to see who's who in the study.

Speaker Change: But so far we have seen very little area in the.

In the long term extension.

Speaker Change: Yes.

Gary: Cool. Thanks for the question. Yep.

Speaker Change: Earlier days with the extension study milestone.

Speaker Change: Inferences from those percentages would be.

Speaker Change: Difficult.

Avi Novak: Thank you. One moment for the next question. And our next question is coming from Nina Ritio-Garg of Dorche Bank. Your line is open. Hi, it's Avi Novak on the line for NENA.

Speaker Change: Thanks for the questions.

Speaker Change: Yes.

Speaker Change: Thank you one moment for the next question.

Speaker Change: And our next question is coming from Neena <unk> Garg of Deutsche Bank. Your line is open.

Avi Novak: Thank you for taking our questions. So on the ABC of technology, can you discuss how your transfer and approach differs from other transfer and base delivery platforms? And then also on Invoke2, given what you know about the AL-002 mechanism, which biomarkers do you see as being most likely to be correlated with improvement on CDR boxes or any other clinical endpoints? Thanks. I can start with ABC technology, and then Gary can address your second question.

Speaker Change: Hi, its Bob that's on the line for any and I. Thank you for taking our questions. So on the ABC of technology can you discuss how you're transferring to approach differs from other transfer based delivery platform and then also on the Seo given what you know about the al two mechanism, which Biomarkers do you see as being low.

Bob: Likely be correlated with improvement on CVR sum of boxes or any other clinical endpoints.

Speaker Change: I can start with the ADC technology and then Gary can address your second question. So in terms of our BBB approach. It implies a versatile black bean bag, yet carrier technology, which uses a suite of fragments that target both TFR.

Sarah: So, in terms of our BBB approach, it employs a versatile brain barrier carrier technology that uses a suite of fragments that target both TFR and CD98 heavy chain. What we found is that, thus far, we're getting about tenfold increases in brain concentrations utilizing these multiple cargoes. I think what's unique about our technology is that it is an adaptable technology, and it's sort of modular, and it's customizable based on the requirements of therapeutic affinity, valency, and format, and we can match that to a variety of cargoes. We use bi-specific formats, and we are also able to customize and make adaptations to the FC portion and have been able to sort of tweak a variety of ranges of affective function as well as half-life.

Speaker Change: <unk> 98 heavy chain what.

Gary: What we've found is that thus far we are getting about 10 fold increases in brain concentrations utilizing these.

Gary: These multiple cargos.

Gary: What's unique about our technology is that it is an adaptable technology and its sort of modular and customizable based.

Gary: Based on the sort of the requirements of therapeutic affinity Balan CE and format and we can match that to a variety of.

Gary: Cargoes.

He used by specific formats, and we are also able to customize and make adaptations to the FC portion.

Gary: And have been able to sort of tweak a variety of ranges of effector function as well as our half life.

Sarah: As we said in the call, you know, our safety and efficacy studies in non-human primates thus far suggest a favorable safety and efficacy profile even when we have FC engaged. And we will be, by the way; we will have a webinar. So I don't, the date's not set, but sometime this summer, which we'll go into a lot more detail on our technology. So please do join us. And I'll pass it to Gary. What was it?

Gary: As we said in the call in our safety and efficacy studies in nonhuman primates.

Gary: As far as suggest a favorable safety and efficacy profile, even when we have FC engagement.

Gary: And we will be by the way, we will have a webinar.

Gary: I don't the dates are set but sometime this summer.

Gary: We'll go into a lot more detail on our technology, So pleased to China at that time.

Gary: Okay.

Gary: And I'll pass it to Gary.

Gary: What was that question? I'm sorry. Yeah, so just for Invoke 2 and given what we know about the ALO2 mechanism, which biomarkers do you see as being most likely to be correlated with improvement in CDR from the boxes or, more generally, a clinical outcome? Well, again, those would be the biomarkers of Alzheimer's path physiology. Most importantly, I think the Tau biomarkers. We will have TauPET, which will be a Tau PET substudy. But we will also have plasma biomarkers on everybody in the study, so P217 and, hopefully, the microtubule binding region assay as well. So this will, you know, this will give us a that the Tau biomarkers are the ones that correlate most closely with clinical outcomes and really can be seen, I think, as sort of a summing up the effects, all these hypothetical effects of benefits of healthy microglia on slowing the disease progression. Great, thank you, and congrats on the quarter.

What was it what was that question I'm sorry.

Gary: Yes.

Gary: Sure.

Gary: Given.

Gary: Given what we know about the allo, two mechanism, which biomarkers do you see as being most likely to be correlated with improvement in ADR sum of boxes or more generally.

Gary: Yes.

Speaker Change: Sure sure.

Speaker Change: Well again that would be the biomarkers of Alzheimer's pathophysiology, most most importantly, I think.

Speaker Change: The Tau Biomarkers.

Speaker Change: Both will be we will have tau pet, which would be a tau pet sub study.

Speaker Change: But we will also have plasma biomarkers on every on everybody in the study with <unk> hundred seven and hopefully microtubule binding region assay as well.

Speaker Change: So this will.

Speaker Change: This will give us that.

Speaker Change: Really the Tau Biomarkers are the ones that.

Speaker Change: Correlate most closely with clinical outcomes.

Speaker Change: It really can be seen I think is sort of a.

Speaker Change: Summing up the the effects all of these.

Speaker Change: Hypothetical effects of healthy benefits of healthy microglia.

Speaker Change: Slowing the disease progression.

Speaker Change: Okay.

Speaker Change: Alright, great. Thank you Alan congrats on the quarter.

Speaker Change: Yes.

Gary: Thank you. One moment for the next question. And our next question is coming from Thomas Shrader, of BTRG. Your line is open. Good afternoon, this is Salman from Saudi Arabia for Tom.

Speaker Change: Thank you.

Speaker Change: Thank you one moment for the next question.

Speaker Change: And our next question is coming from Thomas Schrader.

Thomas Eugene Shrader: Oh <unk>.

Thomas Eugene Shrader: <unk> Your line is open.

Thomas Eugene Shrader: Hey, Good afternoon. This is Tom on for Tom.

Salman: So for the ongoing Phase II Progress 80 study, is there a reason to perhaps stratify these patients based on... baseline programming levels for a possible self-analysis team feature? Yeah, thanks for the question. We did not do, and we're not doing that.

Thomas Eugene Shrader: So for any ongoing face to progress ADP study is there a reason to perhaps stratify patients based on.

Thomas Eugene Shrader: Baseline program level or any possible subset analysis in future. Thank you.

Thomas Eugene Shrader: Okay.

Speaker Change: Yes, thanks for the question.

Speaker Change: We did not do not doing that and thats because it.

Gary: And that's because the part of the evidence in favor of, or in support of this mechanism is that even modest changes in progranulone levels increase the risk of Alzheimer's disease, and so we didn't believe it was, you know, it would be necessary, and our hypothesis is that this would be effective in slowing disease progression regardless of your baseline progranulone levels. There's also animal data, which maybe Orna may want to speak more about, that shows that in various animal models of Alzheimer's disease, just increasing progranulone itself is protective against disease progression. One moment for the next question. And our next question will be coming from Ananda Ghosh, of H.D. Wainwright.

Speaker Change: Part of the evidence in favor.

Speaker Change: Supported this mechanism is that even even modest.

Speaker Change: Mutations that cause even very modest effects and.

Speaker Change: And for granular levels increase the risk of Alzheimer's disease.

Speaker Change: And so we Didnt believe it was it would be necessary.

Speaker Change: And our processes is that this would be effective in slowing disease progression, regardless of your baseline for granular levels.

Speaker Change: Animal data whichever you may want to speak more to that shows that in.

Speaker Change: Various animal models of Alzheimer's disease that just elevating pro granular itself is protected against.

Speaker Change: Disease progression.

Speaker Change: Great. Thank you.

Speaker Change: One moment for the next question.

Speaker Change: And our next question will be coming from Amanda Goose.

Ananda Ghosh: Your line is open. Hey, hi. Congratulations on the quarter. You know, given the biology of TREM-2 and from your own ARIA data, I think there's little doubt that experts believe. There's little doubt about the fact that TREM-2 might be involved in plaque removal. However, one question which I have, and you know, that's based on Vikanema and Donanema and also a lot of questions on tau biomarkers today here. You know, given the data from those two trials and the recent publication validating plasma P-tau 217, do the MRI, the TauPET, the TauPET eBeta data along with the plasma Tau biomarkers put you into a position where you can negotiate an accelerated approval pathway which, strategically, might be very similar to the CalSOTY, you know, CalSOTY approach? So that's the question.

Amanda Goose: H C. Wainwright your line is open.

Amanda Goose: Hey, congrats on the quarter, given the biology of trend too.

Amanda Goose: And from your own or your data.

Amanda Goose: There's little doubt that experts.

Amanda Goose: <unk> believes there is little doubt on the fact that the train two might be involved in <unk> 101 question, which I have that's based on becoming Orlando number and also a lot of questions on Tau Tau Biomarkers to day here.

Amanda Goose: Given the data from those two trials and a recent publication value.

Amanda Goose: Validating plasma.

Amanda Goose: <unk> to $1 seven.

Amanda Goose: You don't do the MRI.

Amanda Goose: Pulp at the sulfate <unk>, along with the plasma Biomarkers puts you into a position where you can negotiate an excellent third approval pathway.

Speaker Change: Strategically you might be very similar to the account Saudi.

Speaker Change: No.

Speaker Change: So the approach so that's the question. Thank you.

Gary: Thank you. Yeah, thank you. So if I understand your question, you're wondering whether based on changes or just treatment-related changes in TauPAD or on TauBiomarkers could that be the basis of an accelerated approval approach? If there is a, you know, if there is a clear, clear sign that there is a, you know, a remarkable change in the plasma TauBiomarker based on plaque removal, is there a potential for an accelerated approval pathway similar to Calsodia? Yeah, I would never say no.

Speaker Change: Yes. Thank you.

Speaker Change: Yeah.

Speaker Change: So if I understand your question, you're wondering whether based on changes or just or treatment related changes on tau pet or on Tau biomarkers.

Speaker Change: Could that could that be.

Speaker Change: The basis of an accelerated approval approach.

Speaker Change: Right.

Speaker Change: There is a clear clear sign that there is a remarkable change in the plasma biomarker based on the plaque removal.

Speaker Change: Is there a potential for accelerated approval pathway similar to Cal Saudi approach.

Gary: And I would say that when we open this up and we see what we have, based on the robustness of the findings, we would certainly, if we thought that it was robust enough, we would certainly consider that. We've also had questions about, well, if we see very significant amyloid lowering, could that itself, could that also be, you know, and again, I think a way of going at this differently. That was not the original intention of this trial.

Speaker Change: Yeah.

Speaker Change: I would never say no I would say that.

Speaker Change: This up and we see we see that we have based on the robustness of the findings.

Speaker Change: We would certainly.

Speaker Change: If we thought that it.

Speaker Change: Was robust enough, we would certainly consider that.

Speaker Change: We've also had questions about well if we see if we see very significant amyloid roaring because that itself could that also be.

Speaker Change: And again I think.

Speaker Change: They are going to at this differently.

Speaker Change: So I think the original intention of this trial and.

Gary: But of course, when we open it up and we see what we have, if we think that there are potential paths forward, we will certainly explore them. Thank you. And our final question for today will be coming from Graig Suvannavejh of Mitsuhu Securities. Your line is open. Graig, are you there?

Speaker Change: But of course, when we open it up and we see what we have.

Speaker Change: If we think that there are potential pass forward, we will certainly explore them.

Speaker Change: Thank you.

Speaker Change: Thank you.

Speaker Change: And our final question for today will be coming from Greg <unk> of our Navy.

Greg Harrison: <unk> Securities Your line is open.

Operator: www.shrader.com. I would now like to go ahead and call and turn the call back over to Mark Grasso for final remarks. Thank you, Operator, and thanks, everyone, for the thoughtful questions. Before we end the call, I'd just like to share that we'll be participating in a number of upcoming conferences, including TD Cowan's 44th Annual Healthcare Conference on March 5th in Boston, Laring's 2024 Global BioPharma Conference on March 12th in Miami, Barclay's Global Healthcare Conference on March 13th in Miami, and Stiefel's CNS Days on March 19th. Thank you again for We'll now conclude today's conference call. This concludes today's conference call. You may all disconnect.

Greg Harrison: Greg are you there.

Speaker Change: Robyn.

Speaker Change: I would now like to go ahead and turn the call back over.

Speaker Change: Two more questions for final remarks.

Greg Harrison: Thank you operator, and thanks, everyone for the thoughtful questions before we end the call I'd like to share that we will be participating in a number of upcoming conferences, including TD Cowen 44th annual Healthcare conference on March 5th and Boston Leerink 2024, Global Biopharma Conference on March 12th in Miami Barclay.

Speaker Change: <unk> Global Health Care Conference on March 13th in Miami, and Stifel. CNS days March 19th. Thank you again for your time and attention. We will now conclude today's call.

Speaker Change: This concludes today's conference call you may all disconnect.

Mark Grasso: The lyrics are in the video description.

Speaker Change: Okay.

Speaker Change: [music].