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spk02: Good afternoon, ladies and gentlemen, and welcome to the Elector second quarter and mid-year 2024 earnings conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1-1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 1-1 again. As a reminder, this conference call is being recorded. I would now like to turn the call over to Katie Hogan, Senior Director of Corporate Communications and Investor Relations. Please go ahead.
spk13: Thank you, Operator, and hello, everyone. Earlier this afternoon, we released our financial results for the second quarter, 2024. The press release is available on our website at www.elector.com. And our 10-Q is filed with the Securities and Exchange Commission this afternoon. Joining me on the call today are Dr. Arnon Rosenthal, co-founder and CEO, Dr. Sarah Kankari-Nitra, President and Head of Research and Development, Dr. Gary Romano, Chief Medical Officer, and Dr. Mark Grasso, Chief Financial Officer. After our formal remarks, we'll open the call for Q&A. I'd like to note that during this call, we'll be making a number of forward-looking statements. Please take a moment to review our slide 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. Arnon?
spk00: Thank you, Katie. Good afternoon, everyone. We appreciate you joining our conference call today. I'll start by highlighting electors' key initiatives during the first half of 2024. Then, I'll invite Gary to discuss our later stage clinical program. Next, Sarah will share the progress we believe we have achieved with Electros Brain Carrier, our proprietary versatile blood bank barrier technology platform. Afterward, Mark will provide an update on our financial results and milestone outlook. During the first half of 2024, we remain committed to advancing our maturing pipeline and are setting the stage for a transformative period ahead. Specifically, we continue to prepare for the data readout from the AL002 phase 2 trial in VOG2 expected in Q4. AL002, our novel TRUMP2 agonist, aims to enhance TRUMP2 signaling and activate the healthy and beneficial role that microglia play in the setting of neurodegenerative diseases. This immunoneurology approach leverages multiple mechanisms of healthy microglia to protect the brain against Alzheimer's disease, potentially offering an efficacy advantage compared to current therapies that target individual misfolded proteins. L002 is the most advanced TRM2-activating candidate in clinical development worldwide, with potential as a monotherapy or as an add-on therapy with anti-amyloids. Today, we will discuss the patient baseline characteristics reported for INVOQ2 trial at the Alzheimer's Association International Conference in July. These characteristics confirm a representative study population that enables testing of the effect of AL002 in early Alzheimer's disease. We will also delve into the multiple clinical trial imaging and biomarkers readouts for the INVOQ-2 trial, our common close design and statistical PMMRM analysis, and our long-term extension study. all of which were designed to strengthen the trial analysis. Additionally, Gary will share our thoughts on what the successful data readout looked like. In February 2024, the FDA granted breakthrough therapy designation to latosinamab for the potential treatment of STD with GRN mutation. You may recall that latuzinamab is a monoclonal antibody that elevates the level of the immune regulatory protein progranulin by blocking sotilin. The breakthrough designation had provided the opportunity for increased interactions with the FDA on this program. And now we have additional clarity on how key biomarkers may support our path to a potential regulatory submission. We will provide more details on this FDA feedback during today's call. Looking ahead, we believe that we are on track for the pivotal phase three data readout from InFRONT3 trial in late 2025, early 2026, and we plan to share more specifics soon. Enrollment continues in the Progress-AD Global Phase II clinical trial of AL-101 for early Alzheimer's disease, with dosing initiated early this year. Like latinuzumab, AL-101 elevates progranoling levels but offers a distinct pharmacokinetics and pharmacodynamic profile suitable for broader indications. Furthermore, in June, we introduced Electro Brain Carrier, ABC, our proprietary blood-brain barrier technology platform. ABC enhances the delivery of therapeutic agents with greater penetration and efficacy at lower doses with the goal of reducing costs and improving patient outcomes. The introduction of ABC represents a significant advancement in our capabilities to address these challenges of drug delivery in neurodegenerative diseases. To summarize, we continue advancing genetically validated first in class and best in class drug candidates for Alzheimer's disease, frontotemporal dementia, and other indications. By targeting genetic pathways Implicated in all degenerative diseases and combining innovative science with emerging technology, we continue to strive for a world where degenerative brain disorders are a relic of the past. At this time, I'll turn the call over to Gary.
spk02: Thank you, Arnon. I'm pleased to provide further insights into our later stage clinical portfolio, focusing on our advancements with AL002 and our progranulin programs. I'll begin with AL002. As a reminder, our ongoing INVOKE2 Phase 2 trial, which was fully enrolled in September 2023, is a randomized, double-blind, placebo-controlled, common-close study evaluating up to 96 weeks of treatment with AL002 in 381 participants with early Alzheimer's disease. This trial includes three doses of AL002, which demonstrated robust target engagement and increased microglial signaling in our phase one study. At the Alzheimer's Association International Conference, or AAIC, last week, Elektor presented participant baseline characteristics for INVOKE2. As Arnon mentioned, the baseline clinical assessments confirm enrollment of the intended population of participants with early Alzheimer's disease. The clinical diagnosis at enrollment was mild cognitive impairment due to Alzheimer's disease for 67% of participants, and mild dementia due to Alzheimer's disease for 33% of participants. Notably, participants with baseline amyloid assessments demonstrated a mean centilloid level of 100.1, aligning with expectations for early Alzheimer's disease cohorts. This data marks an important milestone in our global phase two trial. which aims to evaluate the safety and efficacy of AL002 while testing the hypothesis that this first-in-class TREM2 agonist may slow the progression of Alzheimer's disease. We are on track for the INFOQ2 data readout in the fourth quarter of 2024. Today, I'd like to describe the trial's outcome measures, our statistical analysis approach, our long-term extension study, and the expected trial outcomes. The primary clinical outcome is the CDR sum of boxes. We are also collecting secondary clinical and functional outcome assessments, including the ADAS-COG13 and ADCS-ADL-MCI, from which we will derive treatment effects on the Integrated Alzheimer's Rating Scale, or IDRIS. This trial will also deliver a robust biomarker package, assessing target engagement, treatment effects of microglia, and treatment effects on Alzheimer's pathophysiology. Target engagement will be assessed by measuring treatment effects on CSF levels of soluble TREM2. You will recall that in our phase one healthy volunteer study following single doses, we saw dose-dependent reductions in CSF soluble TREM2, including changes from baseline exceeding 50% at our highest doses. Treatment effects on microglial signaling will be assessed by measuring levels of CSF1R, SPP1, and IL-1RN, which reflect proliferation, survival, and phagocytotic activity of microglia. As previously reported, we saw treatment effects on each of these pathways after single doses in our Phase I study. We are also exploring omics assessments of treatment-related changes in microglial subtypes. Treatment effects on Alzheimer's pathophysiology will be assessed with CSF and plasma biomarkers of A-beta and tau, as well as both amyloid PET and tau PET. We will also have biomarkers of astrogliosis, neuroinflammation, synaptic health, and neurodegeneration. The Phase II INVOKE II trial utilizes a common closed design in which participants remain in a double-blind study until the last participant completes 48 weeks of treatment. Earlier enrolled participants continue in the double-blind study for a maximum of 96 weeks of treatment before they are invited to join our long-term extension study. We intend to use a proportional analysis approach, or specifically proportional MMRM, which enables us to use all the data collected in this common closed design trial. This means we will include data from all participants out to 48 weeks and also include additional data provided by the participants who will have had follow up for up to 96 weeks. Efficacy will be calculated as the average treatment effect observed across multiple post baseline visits. This approach increases power, potentially enabling us to reach statistical significance at a smaller effect size. If our drug slows disease progression comparable to the treatment effects of the anti-amyloid antibodies, we may observe a significant treatment effect. Our ongoing INVOKE2 long-term extension study is currently underway for participants who completed the initial treatment period. This LTE study remains blinded to treatment assignment, allowing for an ongoing collection of meaningful clinical biomarker and safety data. Thus far, Approximately 95% of eligible participants from INVOG-2 have enrolled in the LTE study. In this LTE study, we are also assessing the effects of a modified dose titration on the severity of treatment emergent MRI findings resembling amyloid-related imaging abnormalities, or ARIA. Participants who roll over from the placebo in the double-blind trial to active treatment in the LTE will begin titration at a lower dose than was used in the double-blind trial and will also have a slower dose titration schedule. This is intended to explore the effects of starting at a lower dose and using slower titration on the observed treatment-related MRI findings that resemble ARIA. For context, in the INVOKE-2 double-blind trial, dosing started at 15 milligrams per kilogram and dose escalation occurred every four weeks
spk16: during the first three months of the trial.
spk02: Our hypothesis for the INVOKE2 trial is that treatment with AL002 will increase TREM2 signaling, leading to therapeutic restoration of microglial functions that protect against neurodegenerative disease. This includes the clearance of misfolded proteins, such as amyloid, but we also expect AL002 to amplify the broader beneficial effects of healthy microglia on the brain, such as maintenance of synaptic connections, support of astrocyte and oligodendrocyte function, repair and maintenance of the blood-brain barrier and the vasculature, and regulation of immune tolerance. Thus, our expectation is that restoration of microbial function by AL002 will reduce the brain's vulnerability to neurodegenerative disease, and that the INVOK2 trial will demonstrate treatment-related slowing of Alzheimer's disease progression. as demonstrated by a combination of clinical, functional, and biomarker readouts. With its broad and complementary mechanism of action, we expect AL002 to be effective as a standalone therapy and may also demonstrate additive or synergistic effects when used in combination with amyloid targeted therapeutics. We also believe that treatment benefits of AL002 may manifest differently from what we have seen in trials of the anti-amyloid antibodies. For example, with regard to biomarker responses, lowering cerebral amyloid PET signal to the 24-centiloid threshold, which for anti-amyloid antibodies appears to be a necessary condition for clinical efficacy, may not be relevant to this mechanism of action that goes beyond amyloid clearance. Additionally, optimal disease stages for intervention may be broader. Unlike therapeutics targeting amyloid or tau, we do not expect the beneficial effects of healthy microglia to be limited to specific pathophysiological stages of disease. Thus, AL002 may have potential to benefit patients ranging from preclinical Alzheimer's disease through advanced dementia.
spk16: Turning now to our progranulin programs.
spk02: In a recent type B interaction with the FDA, we in GSK received feedback on the potential future biologics license application for latizinimab. The FDA has indicated that it would consider the effects of latizinimab on plasma and cerebrospinal fluid progranulin levels as confirmatory evidence, supplementing the potential clinical effects of latizinimab, pending BLA review. We also aligned with the agency on disease-relevant fluid and imaging biomarkers that may be considered as supportive evidence of clinical efficacy, also subject to BLA review. These include biomarkers of astrocyte function, neurodegeneration, and brain atrophy. Based on the FDA feedback, we remain confident that the totality of evidence, including the primary clinical endpoint and biomarkers, could provide a path to potential approval for latozinumab. Following these productive interactions with the FDA, we believe we are on track for the pivotal in-front three, phase three data readout in late 2025 or early 2026. In parallel, enrollment continues in the progress AD global phase two clinical trial of AL-101 for early Alzheimer's disease. We and GSK are co-developing AL-101 for the potential treatment of more prevalent neurodegenerative diseases. including Alzheimer's disease and Parkinson's disease. At AAIC, our partner GSK presented a poster highlighting data supporting the hypothesis that therapeutic increases of progranulin levels may be an effective treatment for Alzheimer's disease. These findings demonstrate consistent causal associations between increased progranulin levels and reduced Alzheimer's disease risk. across the progranulin gene allelic spectrum, providing compelling genetic evidence for increasing progranulin levels as a potential therapeutic strategy to treat Alzheimer's disease. As we advance these programs, we remain dedicated to harnessing our scientific and clinical expertise to drive forward transformative therapies for neurodegenerative diseases. At this time, I'll turn it over to Sarah for updates on our progress with the Elector Brain Carrier.
spk01: Thank you, Gary. In June, we had a virtual R&D event highlighting our Elector Brain Carrier blood-brain barrier technology platform. At Elector, we've dedicated several years to developing our proprietary, versatile Elector Brain Carrier technology, known as ABC. We are leveraging the ABC platform as a vital tool in our preclinical pipeline and novel drug development. ABC enables us to expand our pipeline to include neurodegenerative diseases requiring enzyme or protein replacement. It enhances our novel antibody pipeline by improving brain distribution, potentially requiring lower doses, and enabling subcutaneous delivery. Additionally, we are also leveraging our ABC technology in the development of second-generation drugs towards our pipeline and validated targets. ABC has been validated with multiple therapeutic cargos. Notably, we've focused on two key transporting targets, transferrin receptor, known as TFR, and CD98 heavy chain. TFR, a well-known ion transport receptor, swiftly delivers cargo to the endolysosomal system, while CD98 heavy chain integral to amino acid transport complexes targets cargo primarily across the endothelial cell surface. Both receptors enable effective delivery of functional cargos, including antibodies and proteins, to targeted cells within the central nervous system. Having multiple receptor targets allows us to tailor brain uptake, optimizing efficacy and safety. Our approach with ABC is distinguished by its versatility, tunability, and translitability. Our ABC technology is versatile and can accommodate a wide range of cargoes, from antibodies to nucleic acids, thus enhancing its application across neurodegenerative diseases. Tunability is core to our technology, utilizing a diverse panel of binders with varying affinities to blood-brain barrier receptors to precisely match different cargos, optimizing therapeutic efficacy while ensuring safety. Additionally, translatability from preclinical to clinical species is a key feature and can be important in accelerating our path to clinical trials. ultimately enabling efficient delivery of innovative treatments to patients. ABC's capabilities underscore electoral commitment to advancing therapies for neurodegenerative diseases by overcoming challenges in drug delivery to the brain, positioning us at the forefront of neurodegenerative disease drug development. Looking ahead, we will continue to provide updates on our ABC programs as they progress, reinforcing our dedication to pioneering new frontiers in brain health. Now, I'll turn the call over to Mark for an update on our financial results and milestone arguments.
spk18: Thank you, Sarah. We summarized our second quarter 2024 financial results in the press release we made available after the market closed today. First, I'll highlight that we remain well-funded to execute our strategic objectives. We ended the second quarter of 2024 with a strong cash position of $503.3 million. Our cash runway extends through 2026, demonstrating robust financial preparedness for future growth and financial strength through the completion of key milestones, including the AL002 Invoke 2 Phase 2 data readout and the pivotal Infront 3 Phase 3 data readout for let us in a map. with the runway coverage extending approximately a year beyond the In Front 3 readout. Turning now to 2024 financial guidance. We continue to anticipate collaboration revenue to be between $60 million and $70 million. We have tightened our total research and development guidance to be between $210 million and $220 million. We have reiterated our total general and administrative guidance to be between $60 million and $70 million. We are well capitalized with a robust cash position and remain focused on advancing our later stage and ABC portfolio. We look forward to providing additional updates as we progress our work. That concludes our prepared comments for today's call. Operator, you may now open the line for questions.
spk02: Thank you. At this time, we will conduct the question and answer session. As a reminder, to ask a question, you'll need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster.
spk16: And our first question comes from Paul Matisse with Stifel.
spk04: Hi there. This is Julian on for Paul. Thanks so much for taking our question. So a couple from me. On trend two, do you mind just reminding everybody What proportion of data from participants out to 48 weeks and 96 weeks and somewhere in between do you expect in this upcoming readout? And also, do you plan on rolling over APOE4 homozygotes that were in the placebo group to your long-term extension study? And then also on latazinamab, can you just clarify what exactly does it mean that the I guess to me it seems a little unusual for a biomarker to be confirmatory evidence of clinical benefit. Usually it's predicting clinical benefit in the absence of clinical data. So any additional color would be really helpful there. Thank you.
spk02: This is Gary. I can take that. So I think your first question was around TREM2. How many patients do we have at the different time points? So all of the patients... All the completers, which we expect to be around 250, will complete 48 weeks of treatment. And then we'll have about half of those will have 72 weeks of treatment. And about a third will have 96 weeks treatment. And I want to just remind you that our LTE remains blinded to original treatment assignment, which means that we'll still be able to collect meaningful data. on biomarkers and safety, but also on clinical outcomes, given the blindness and the fact that, and that will be up, so six months later, we'll have a minimum of 72 weeks of data on all patients, and then six months later, two years of data. Your second question was about the LTE, I think, about rollover of ApoE homozygous. No, we are rolling over the placebo group, which is which like the rest of the study at the current study population does not include APOE4 homozygous anymore. They were, we stopped enrollment early in this study and discontinued them because we saw more severe MRI changes resembling ARIA in the APOE4 homozygous. So they are not rolling over in the LTE. And I think your last question was about latazinamab. What does it mean to be confirmatory evidence of clinical benefit? It means that, you know, if we have a clinical, clinically, you know, a positive result on the clinical, primary clinical outcome measure, which is the CDR, that the CDR, FDD, FDLD, NAC, you know, it's the, basically a CDR with two additional modules for behavior and language difficulties, which FDA, FDD patients have. And what it means is that, you know, we, we discussed some, some specifics about some of the biomarkers, imaging and fluid biomarkers that we would use, including a GFAP and NFL and region of interest, volumetric or volumetric MRI. And, that they would be, you know, they would, if we were to see effects on those biomarkers, that would be added, you know, confirmatory evidence of the effect on the clinical outcome measure. It does not mean in this context that it would be, that the biomarkers would be surrogates for the clinical outcome measure. However, that said, I mean, we are also fully cognizant that you know, there are many similarities here in FTD to drugs like tofersin that was approved based on an accelerated approval based on very, you know, some of the same biomarkers, NFL predominantly. And likewise in this study, you know, we see these biomarkers are prognostic and FDA, you know, we had a discussion with this about those similarities. And so, you know, if If our, for some reason, and we don't expect this, but if, especially based on our phase two data, which was very promising, we expect that if we did, if we were disappointed by the clinical outcome, but we saw directional effects, I mean, we think that a backup strategy could be an accelerated approval approach. We have not discussed that with FDA yet, but I think that they're, you know, we're encouraged by their endorsement of the biomarkers that we
spk16: Got it. Makes sense. Thanks. Appreciate it. One moment for our next question.
spk02: And our next question comes from Alec Stranahan with Bank of America.
spk11: Hi, this is Susan on for Alec. He had a question about InVoke2. How should we be thinking about patients enrolling in a long-term extension study for INVOK2 in terms of tolerability and efficacy?
spk02: Yeah, thank you, Susan. So how do we think about patients enrolling in LTT around efficacy and safety? Well, first, I have to tell you that we're very pleased by the fact that up to this point, 95% of patients that have been eligible to roll over, and that's most of the patients by far, have decided to do so and are now in the LTE. Some have actually completed the LTE. And in terms of efficacy, we will be, we don't know, we're still blinded and we haven't looked at efficacy. We will include some of the LTE data that will have been collected up to that time in our sensitivity analysis at the time later this year when we lock the database and have a look at the data. With regard to safety, you know, there really haven't been any significant safety signals beyond the, you know, the MRI signal that resembles ARIA, which we've described in a lot of detail. And also, you know, a small number of infusion reactions, which is not to be unexpected with a monoclonal antibody.
spk17: Thank you, Susan.
spk16: Operator, I think we're ready for the next question. One moment for our next question. And our next question comes from Jeffrey Hung with Morgan Stanley.
spk05: Hi, this is Michael Riad. I'm for Jeff Hung. Thank you for taking our questions. Going back to the baseline invoke data, so two-thirds had mild cognitive impairment and a third had mild dementia. but you also saw mean and more like pet centeloids of around 100 baseline. Are you able to say whether that differed between the two populations in terms of cognitive impairment versus dementia? And also, it's not a full capture of the total trial population. Is that something that will get resolved? Thanks, and I have a follow-up.
spk02: Yeah, so... I can't tell you, we don't have the data broken down by the MCI and and mild AD regarding the seniloid levels. I don't have that. We just looked at the aggregate of seniloid levels. And, you know, we, let me see, did I miss your other question? I didn't catch the question about full capture. I didn't quite follow what you were asking.
spk05: Oh, sorry about that. I just meant, like, I thought it was, like, in the low, like, mid-200s, and the trial had enrolled more patients. I don't know, like, is mean amyloid PET at baseline something that would be captured through the whole population or just the, like the 244?
spk02: Yeah, so at the, this was baseline characteristics. So this was, what we reported out on was the number of patients that was where the patients that had used amyloid PET for inclusion and therefore had a baseline amyloid PET scan. So that would include you know, everyone up to that point for which we had data, you know, which would be everyone because they were fully enrolled. Yeah, so that's the – I hope that answers your question.
spk05: Yeah, no, that's very helpful. And then just as a quick follow-on, like what sort of follow-up, what would you think is the expectations for samloid reduction in INVOQ?
spk02: That's a good question. So, you know, since we see this MRI finding that resembles ARIP in every manner, you know, we wouldn't be surprised if we're lowering amyloid. We also wouldn't be surprised given that the fact that this is a, our, we believe that AL002 will restore microglial function. And we know that microglia are, you know, involved in compacting and also clearing amyloid and other misfolded proteins during and under regular conditions and also are involved in removal of amyloid after they get tagged by anti-amyloid antibodies. So it doesn't surprise us that we would see that. In terms of the expectation, you know, we don't know yet. And, you know, we haven't yet looked. But I would tell you that we don't see I think this is really an important point. This is a truly different mechanism than anti-amyloid antibodies. And it has, as we described in our presentation, by restoring microglial function, we're restoring many different downstream mechanisms by which microglia preserve brain health. So this is really not intended to be just an amyloid lowering agent. If we do or do not reach the amyloid, you know, the 24 centeloid level that seems to be a necessary condition for clinical efficacy for the anti-amyloid antibodies, that's not going to bother us. And we're not going to make a decision based on that because, you know, this really goes beyond amyloid clearance, this mechanism.
spk05: Thank you so much. I really appreciate that.
spk02: Yep.
spk16: One moment for our next question. Our next question comes from Pete Stavropoulos with Cantor Fitzgerald.
spk14: Hi, this is Samantha on the line for Pete. Thanks for taking our questions. Firstly, for TREM-2, can you give us an idea of what to expect for the first data release next quarter? What's the bar for moving this program forward into a later stage study? Will it be biomarker driven or do you need to see a clear signal of clinical efficacy? And regarding safety monitoring, is it safe to assume that ARIA-like observations have been minimized due to the protocol changes? Has there been any new KOL feedback on what might be driving these observations? And finally, regarding the ABC technology, could you describe the tissues or cell types where CD98 is expressed and outline any theoretical risks associated with targeting CD98? Thanks so much.
spk02: Okay, thanks. Good questions. Thanks, Samantha. So what to expect in terms of what data we're going to report, we'll have a press release, and that press release will include not only the typical top line primary clinical outcomes and and safety, but we're also going to include data on the relevant biomarkers. As I said, this is, we're making a decision based on a combination of clinical, functional, and biomarker readouts, and we have lots of biomarkers. So all of those that are relevant to making a decision, you know, particularly the Alzheimer's physiology biomarkers will be included, we'll be reporting out on We intend to report out on all of those at the same, you know, with the press release, not just top line. And what is the bar to advance? I just said it, right? It's some combination there of, and seeing consistency across those clinical and biomarker outcomes. that showing that we are slowing disease progression because that's that, that in the end of the day, that's, that's, that's what we're up to do. So it's not going to be, you know, it's not going to be about hitting a P value or on just clinical outcome measure that, you know, that's if we do or don't, if we see directional effects, they are consistent with biomarker, you know, directional effects showing slowing of disease progression for us, that's a win. And that, that's, that's a, we'll be very excited to see that and advance the compounds. You also asked about ARIA. Do we think it's minimized? Well, what we do know is that after we dropped the APOE4s, we then added MRI surveillance. And MRI surveillance, actually, we were doing it every four weeks before each dose of titration for the less often after that. We know, you know, that likely increases the amount of area you're going to find because you're looking every four weeks for radiographic area, which is 90% of the area. Lilly, by the way, reported that in their banana map phase three program that they, when they added area surveillance, increased the area surveillance, they saw more area. Also, they saw, in addition to seeing more higher incidence, they also found that the severity was reduced. And we've also observed that, as I said, the incidence and severity of ARIA has actually come down for us in our study under the current population. Is it minimized, meaning is that as low as it can go? I don't know. We don't know that for sure, but I can tell you that in our long-term extension, one of the things that we're exploring is whether starting at a lower dose and titrating more slowly, akin to what they've been doing in the amyloid, anti-amyloid antibody trials, could reduce the area signal. So we hope to learn that as well in our long-term extension study. And what was the mechanism? I'm sorry, I think the last question was something about what about the mechanism? Everyone we show this to says this has to be related to amyloid clearance. I'm kind of conservative, so I'll wait till I see the data, but I think that's a good bet. And I think there's a CD98 question for Sarah.
spk00: According to the human protein atlas, CD98 is expressed in endocrine tissues, in the pancreas, in the kidney, in genitalia, and a little bit in the skin. So yeah, we will be looking if there's any adverse effects in these tissues. In the brain, CD98 is expressed. higher in supporters in microglia and atrocytes and in lower levels in neurons outside of the endothelial cells, which enables using it as a blood and burial transport.
spk17: This is so helpful. Thank you so much.
spk16: One moment for our next question. Our next question comes from Yaron Verber with TD Cowan.
spk08: Hi, this is Brendan on for Yaron. Thanks for taking the questions, guys. Actually, just a quick one on the potential of the opt-in payment. Can you maybe just remind us what the timing is to potentially book that? If the data comes out in Q4 and looks good, would you expect to book that after the Phase 2 data, maybe in Q1? Are there other gating factors there? And just kind of let us know how you would report that. And then, honestly, just looking at the deeper pipeline, I was just wondering which of the target programs you might expect to enter the clinic first when you think that might happen. Thanks.
spk18: Yeah. Thanks for the questions, Brendan. So, as it relates to the option payment with AbbVie, as you recall, That's at their option, $250 million at the end of the phase two. So we're aligned with them around the concept study package, and we plan to be sharing that package with them at the end of this year, Q4 of this year. And if they have 90 days post their acceptance of that package to decide if they're opting in, so that would put the payment, you know, towards the end of Q1. Early Q2 is our expectation currently. And then your second question around which of the programs in our earlier portfolio will be advancing and which is the most advanced. We have a number of disclosed programs and a number of undisclosed programs. And we look forward to providing you updates around that portfolio as next year progresses. in the coming years. We haven't specifically made a statement at this time as to which one is advancing first.
spk17: Hopefully that helps, Brendan.
spk16: Yep, that's great. Thanks, guys. One moment for our next question. And our next question comes from Carter Gould with Barclays.
spk06: Good afternoon. Thanks for taking the question. I guess first off, I want to be clear on exactly what's sort of being messaged coming out of that Type B meeting. It's appreciating your affirmation of confidence in the primary endpoint, but it sounds like this is a contingency strategy in the context of a potentially equivocal data on the primary. Is that a fair characterization, and does this in any way represent an evolution of your regulatory strategy? on that program. And then I guess just to follow up on coming out of INVOK2, it sounds like there'll be a separation of data and path forward. So I guess, again, is that sort of a fair characterization that we shouldn't expect any sort of commitment on moving the product forward necessarily when we get the data? And I guess alongside that, as we think about AbbVie and their decision process, they did recently deprioritize or discontinue their A-Beta program. How do you view that, and if there's any read-through to 002? Thank you.
spk18: Thanks for the question, Scott. Maybe, Gary, you can take the first question, and I'll take the latter, too.
spk02: Yeah, yeah, sure. So, Carter, thanks for your question. No, this really is not a contingency strategy. We are committed and we're optimistic that, you know, we can get a full approval based on the primary outcomes, secondary outcomes, and the biomarkers. Our questions were really, you know, are these the biomarkers? You know, there's a lot of biomarkers one could look at. We felt that the ones that we proposed were biomarkers that if we were to see effects, these are biomarkers that are prognostic to begin with. So, you know, if you see changes in NFL or GFAP even before there are symptoms, you see changes in volumetric MRI even before symptoms. So it's a prognostic biomarker. We don't know yet whether it is a surrogate marker, but, you know, but we would imagine that, you know, because you see these changes even in advance of clinical symptoms, that changes in the trajectories of these biomarkers should support the clinical outcome. This is a single study. It's a rare disease, so it's a relatively small study. It's 100 patients. And so, you know, we're always thinking and looking about how to devise our statistical analysis plan in a way that, you know, can best show that the drug is providing benefit. And we thought these were important questions to ask. If they didn't think these biomarkers were relevant or good enough or whatever, then we would have maybe think differently about our SAP, but we were very encouraged by this information. We really are committed for a full approval based on the totality of the data.
spk18: Yeah, and I think your second question, Carter, related. So, we were answering the question the prior analyst was asking about the, I think, the earlier pipeline in which programs would advance NACs, not referring to TRMM 2. You know, that program, obviously, you know, subject to ATVs, Opt-in decision, that would be a component, but we're looking forward to advancing that. We expect the next stage would be a Phase 3. If they opt-in, they would be taking on that Phase 3, and we share 50-50 in the costs and also the profits as that program advances. And remind me, your third question, Carter?
spk06: Again, any read-through from Abby's decision to deprioritize and discontinue their A-beta program? Sort of, on some level, you could say that's narrowing their Alzheimer's portfolio. And do you see any read-through then to around their interest in 002? Thank you.
spk18: Yeah, yeah. It's really hard for us to speculate there. Maybe they didn't see the differentiation they were looking for with that A-beta program relative to what else is out there. Again, you know, we remind, you know, the broader mechanism and, you know, the complementary role that activation of microglia can play. So, we don't necessarily see a read-through there, but, you know, that's, you know, our speculation. What we can say is, you know, we're very aligned with AbbVie, including around, as I mentioned, you know, as Gary's highlighted, you know, the phase two data readout and the concept study package that's associated with that.
spk17: Thank you.
spk16: One moment for our next question. And our next question comes from Tom Schrader with BTIG.
spk03: Good afternoon. Thanks for taking the question. They're on Progress AD, the trial with 101. Have you seen, or are you going to update us if you're going to see, if you've seen the MRI signal characteristic of ARIA? It's obviously interesting here, but at some level, doesn't it de-risk the entire progranulin program if you did see some ARIA?
spk02: Yeah, that's a good question, Tom, as always. You know, we have, we don't have any recent, well, we, because this mechanism of action involves uh we think involves microglia uh uh and you know we have built into the study uh uh mri surveillance to look and see if we if we have area um i can tell you that you know we have we haven't seen you know we haven't seen any such signals thus far study it's early days uh with that study um would it de-risk the program you mean in the sense that it would um
spk03: So, yeah, extracellular sordaline does what it's supposed to.
spk02: Yeah, yeah, I suppose so. I mean, I think, yeah, I mean, I think in the same way that we think about it in AL002, it would be in some ways encouraging about biological activity. But, you know, so far we just, you know, we're looking mostly, you know, to make sure we don't miss a safety signal that we need to keep an eye on. But we haven't seen anything else yet.
spk03: And real quick, is increasing progranulin to high levels based on the biology that you guys are so into, is that as broad an effect as increasing TREM2? It almost seems like a step backwards, that you're fixing the lysosome and hoping everything else follows, rather TREM2 forces everything. Is that a fair characterization?
spk02: Arnon, I'm happy to answer that, or if you want to speak to it.
spk00: Yeah, it is a different mechanism, but prognoling also has a very broad range of activities. It is a liposomal chaperone, as you said. It enhances liposomal activity, which is a critical component in fighting misfolded protein, but it's also a survival factor for multiple types of neurons. It sort of enhances sort of neuronal activity. So we think that, yeah, these are different mechanisms, and we think that because neurodegeneration is sort of such a large unmet need, it's worth testing multiple mechanisms. We don't think that progranoling is less broad or is sort of similar to anti-abeta antibodies, for example. We think that progranoling is sufficiently broad to address multiple disease pathologies. Okay, great.
spk16: Thanks for the details. One moment for our next question.
spk02: Our next question comes from Miles Minter with William Blair and Company.
spk15: Hi. Yeah, you've got Sarah on for Miles. Congrats on the progress, and thanks for taking our questions. So can you just remind us whether all doses tested and invoked to would potentially be therapeutic? And as it relates to your powering assumptions, are you expecting to pool those treated patients or consider each dose arm individually? And second, now that we've seen the baseline characteristics, in your view, how do these patients compare to those enrolled in other AD therapeutic trials we've seen regarding severity, stage of disease, and biomarkers? And do you think the entire range of dosing, including 48-week will be long enough to see a measurable function decline in the placebo group to potentially separate from those treated patients.
spk02: Wow, they're great questions. Thank you. So do we think all doses are therapeutic? Well, yes, because in our phase one study, we saw... Target engagement, so reductions in soluble TREM2, they were highest in the top two doses where we saw greater than 50%, but they were still robust in the low dose that we're testing and even lower than that. So based on that, I think that that is... it would be therapeutic. We also saw increased microglial signaling across multiple pathways, IL-1RN, I think we mentioned this in the call, and CSF-1R and SVP-1 at all those doses. So yeah, we do think that those are potentially therapeutic. In terms of the analysis, so we will look at each dose versus placebo, but we will also be pooling data. And in fact, the top two doses are are overlapping considerably in their PK. And so we will, that's definitely part of our, you know, a pre-specified, it's a pre-specified analysis that we'll be looking at, definitely. How do the patients compare to the other anti-amyloid antibodies? You know, really right down the middle, I mean, I would say. I mean, the centelloid level is a bit higher than an A-size antibody, lekembe but is it's a little bit lower than what uh that they saw in the nanomab uh the same thing for the distribution of clinical uh diagnosis and and you know based on the data we had it really looked right down the middle so we were very pleased with with that um and i think uh the last question was does the entire range of oh yeah dosing right right so um i i think you're asking about would the with the duration of 48 weeks be enough um you know yeah you know this is One of the reasons for the common cause design here was that this is a novel mechanism. And we can't necessarily expect that the temporal dynamics and treatment effects of restoring microglial function will all happen at the same time right i mean if there are effects on clearing amyloid and synapses we might expect those earlier if there's uh effects by by by restoring the maintenance functions of supporting uh you know the oligodendrocytes and astrocytes and the blood brain barrier and the vasculature immune tolerance those could take potentially they potentially could take longer so you know, we, we do think that 48 weeks, we should, you know, we hope to see something at 48 weeks. Uh, we will have data out to 96 and that's one of the reasons we, we and Abby really wanted to invest in the, uh, in the long-term extension, uh, to be blinded to treatment assignments so that we could get meaningful data even after, you know, even if, uh, after the double blind, uh, we locked the double, the study in the double blind. So, you know, I, I, I think some of those manifestations could be early, but we think that the full effect of this mechanism may, you know, it's possible that it'll take longer to see that. Hopefully, we'll get to see that in those that have data out to 72 weeks and even those out to 96. But, you know, if it's emerging, we'll have the study designed to be able to capture that.
spk15: Makes sense. Thank you.
spk16: Thanks. One moment for our next question. And our next question comes from Ananda Ghosh with HC Wainwright and Company.
spk07: Yeah, hi, thanks for taking the question. I have a couple of questions. The first one is, of course, on the Type B meeting. So, you know, just curious, given FDA's encouraging stand in the Hunter syndrome, you know, where they might consider heparin sulfate as a surrogate biomarker, or if you look at ALS, the two-person example, which... which you mentioned. What has been your takeaway, like how open FDA might be to consider some of the biomarkers like procradulin itself as the surrogate biomarker for the PGRN program going forward?
spk02: Yeah, thank you. I agree with you that there's been a lot of, I think there's been some regulatory concerns flexibility, and certainly when it comes to rare diseases, that they seem to be more so, you know, more so, more flexibility in how they, and especially in considering, you know, biomarkers to be supportive or even enough for an approval. And you gave some good examples. You know, we're encouraged by that, but we still feel that we have we have a very good shot at a full approval with the more traditional approach. That said, you know, if we're disappointed somehow with, you know, the clinical outcome measure here, which, you know, we think we are going to have a really good backup plan, you know, if we see biomarker changes as we expect to see. So, yeah. I think we're encouraged by that flexibility, but a full approval for us is not debatable. It would be better for patients, better for us if we could get a full approval.
spk07: Got it. A follow-up question on the programming program is, At the European ALS Conference, a lot of KOLs actually pointed out that, and now it's kind of well-established, in case of tofacin, you see the NFL drop much before then you see the clinical benefit coming from tofacin in SOD1 mutant patients. So for your progranulin program, have you thought about, is there a way to kind of... to also track that where you see the clinical benefits kind of lags behind the drop in some of the key biomarkers or the way the biomarkers are progressing.
spk02: Yeah, I agree with you. And the same is true in FTD. You see changes in NFL before you see clinical signs and symptoms. Um, that's why in our study, we originally started out, uh, including patients who were asymptomatic, but we knew that we're at risk because they had it for granule and loss of function mutation. And they also had elevated NFL levels. Um, we originally planned to include it in our primary analysis, but, um, but because they were, they're hard to find and we had very fewer of them and because they had a lot of variability to the, to the, um, um, you know, to progression rates. Last year, we went to FDA and EMA, and we proposed to focus on the symptomatic patients for the primary analysis, but we will still analyze that data in the pre-symptomatic patients as a sensitivity analysis. So, and we're very excited about that. You know, we think if it's going to work in symptomatic patients, it may work even better in the early patients, in the pre-symptomatic patients. So, You know, and yeah, we may, we'll see when we look at our data, whether we see changes in NFL that precede, you know, the temporal dynamics of effects on those biomarkers versus the clinical outcomes.
spk07: Got it. And I just have two questions on the TRIM-2. The first one is, you know, both Biogen and obviously Lilly has done this, you know, the low tau, high tau like analysis for their eddy trials. So what have you, like, do you have plans to kind of do a subgroup analysis later on where you are looking at low tau or high tau and to kind of figure out what, you know, how the L002 impacts in this kind of population? And the second is how fast the RAMPAP might be for your titration schedule for AL002.
spk02: Yeah. So, okay. So, about the tau, a question about, you know, will you use tau tercials? Yeah, that's definitely part of our pre-specified analysis. We're going to, we will have P217 in every patient, so we can do it by P217 levels. We will also have tau PET in a smaller subset, but we'll be doing it mostly based on plasma P tau markers. We are going to look at those tercials. That, of course, will tell us give us some indication of whether we are seeing differential effects across the disease spectrum, you know, in low-tau or mid-tau patients or high-tau patients. That said, we really don't expect to see these differences as much with this mechanism than you would with an anti-amyloid antibody where there's more of a defined window of the pathophysiology that may work the best. The second question is about the ramp up. So, you know, in our study, when we went to a titration, it was every four weeks was the increase in dose. And that's why we, as I mentioned earlier, that we were putting in MRI surveillance. We're slowing that titration down and starting at a lower dose in the patients that roll over in the LTE, because we want to learn whether that could be mitigating for the area. Okay. Thank you very much.
spk18: Thanks, Ananda. Good questions. I think we have time for two more here.
spk16: One moment for our next question. Our next question is from Greg Savanovich with Mizzou Securities.
spk09: Thank you very much for taking my question and congrats on the progress. Earlier in your prepared remarks, you had mentioned, I think, the analytical methodology that you will apply to your invoke to trial and I wanted to ask about how that particular methodology might compare with others in Alzheimer's disease. It does seem as if you've taken an innovative approach here with the view that you're hoping to increase the powering of the study, but someone who may not be as well-versed in that methodology, could you just speak to the differences between how others have analyzed their Alzheimer's trials? Thanks.
spk02: Yeah, yeah. So this proportional method that we're using or proportional MMRM, as I mentioned, you know, it allows us to look at, it allows you to, it's really particularly helpful in the common close design where we have patients with different durations of treatment, and we can use all of that data, as I outlined. This is a novel method, but it has been used before in Alzheimer's trials in one of the Diane studies it was used. And also, I believe that really used it as a sensitivity analysis in their phase two and possibly one ASI. I don't remember which study that was. So it is novel, but others have explored it. yeah i i think it's it for us we thought given the common closed design and given um that we were trying to um uh you know make this a really a biomarker rich study we would have a lot of different types of readouts we thought that this would be uh you know the best really and and uh i should say abby you know uh agreed around this design um you know some years ago before the study started so so Yeah, I mean, we'll also do sensitivity analysis with other more traditional approaches, but this is our primary outcome.
spk18: Thanks for the question, Greg. Aubrey, I think we have time for one more.
spk16: Our next question then comes from Corrine Johnson with Goldman Sachs.
spk12: Yeah, thanks, guys. Good afternoon. Maybe could you just talk a little bit, I think I understand, but if you could just like square the comments you've made around thinking the mechanism is related to amyloid clearance, but that you don't have to get the same degree of centroid reduction to kind of see clinical effects. And then maybe you could expand a little bit more on the cash runway guidance, particularly with respect to which activities around the ABC platform are going to be embedded within that timeframe.
spk02: Yeah, so I'll take the first one, Corinne. Thanks, good question. Yeah, so what I was referring to is that, so our hypothesis is that increasing TREM2 signaling triggers a number of other signaling pathways that allow for proliferation of microglia, increased function and survival. And we think that this is going to shift the population of microglia. We know that with aging and with neurodegenerative disease, you have senescence of microglia. So by shifting the microglia to more healthy and active and functional microglia, we'll have all those beneficial effects that come, I won't repeat, that come from microglia, including amyloid clearance and clearance of misfolded proteins. And by the way, it's interesting that we're focusing on amyloid because of the potential, the area-like signal, But, you know, there's lots of comorbidities that are usually seen with Alzheimer's disease. So microglia are not, you know, are not selective for amyloid. They would clear TDP43 and they would clear other alpha-cynically and the like. So, you know, we think this is a, you know, this is why we're so excited about this mechanism. When I say it, you know, it doesn't need to reach the 24 centeloid level. I think for an anti-amyloid antibody, But that's what it does. It lowers amyloid. It looks like there's now plenty, lots of data showing that curve. You've seen the graphs, I'm sure, where they show that you need to get to a certain level before you start seeing clinical benefit. The Gantanerimab study is an example of one that didn't quite get there. And, you know, in Adacatabab, you know, one of the studies didn't get there, didn't have clinical, the clinical data were less robust. So it looks like you have to get down to this 24 centiloid level if that's your mechanism you're using. This mechanism goes beyond that. Yes, we might have amyloid clearance, but we think that all of these downstream mechanisms are at play. And so, you know, we're not going to judge this mechanism of action based just on the amyloid clearance, the amount of amyloid clearance we see. I hope that, did that help or did I answer your question?
spk00: Yeah. I can add to this a little bit. There are data even in human that A microglia in a trauma-dependent manner can contain A-beta without removing it. They form a barrier between the A-beta plaques and the surrounding neurons, and they basically make the A-beta plaques inert. The A-beta plaques can no longer injure the neurons. So you can get therapeutic benefit even on A-beta without removal of A-beta if you recruit the microglia.
spk12: I see. Okay.
spk00: And in addition, yes, as Gary said, the microglia are responsible for replacement of damage synaptic connections. In Alzheimer's disease, up to 50% of the synapses can be damaged. They are responsible for the replacement of damaged myelin. There is significant myelin damage in Alzheimer's disease. They are responsible for direct normal transmission. Without functional microglia, normal transmission is abnormal. So there are a lot of other activities that should translate to clinical benefit independent of a beta pathology.
spk18: And just on the cash runway, guys, Corinne, so we reiterated that our runway is through 2026, and that's, you know, a full, you know, two years beyond the expected TRIM-2 data readout end of this year and, you know, a full year beyond the expected FTD phase 3 readout end of next year and doesn't assume any opt-in from AbbVie or, you know, other milestones or business development. So, you know, we think that's a pretty healthy runway and a strong position as it relates to the electrobrain carrier portfolio. We're going to provide more updates as that program progresses, as those programs progress. We haven't said specifically uh what what that would um advance those programs through but you know you could expect uh that that would be you know through inds on programs correct thank you yeah and this concludes the question and answer session i would now like to turn it back to mark for closing remarks Thanks, everyone, for the thoughtful questions. Before we end the call, I'd just like to share we will be participating in a number of upcoming conferences, including the Morgan Stanley Annual Global Healthcare Conference September 5th in New York, H.C. Wainwright's Global Investment Conference on September 9th in New York, and Cantor's Global Healthcare Conference on September 17th in New York. Thank you again for your time and attention today.
spk16: And thank you for your participation in today's conference. this does conclude the program, you may now disconnect.
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