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spk08: Good day, and thank you for standing by. Welcome to Electors Q4 2023 Earnings Conference Call. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during a session, you will need to press star 11 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.
spk12: 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, Dr. Sarah Kankari Mitra, 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. And thank you for joining Elektor for our first 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 protein, 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. Our investigational drug candidates have the potential to be effective as standalone 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, has the potential to elicit a more potent therapeutic benefit with longer durability and better efficacy at multiple disease stages compared to current therapies against misfolded proteins. 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 electros standing as a pioneer in immunoneurology. Importantly, we completed trial enrollment for our two lead programs. This includes the pivotal and front three, phase three trial of our progranulin-elevating candidate, latuzinamab, in front of temporal dementia with progranulin gene mutation, or FTD-GRN, and invoke two phase two trial of our TRAM2 candidate AL002 in early Alzheimer's disease. In partnership with GSK, we also recently dozed the first participant in PROGRESS-AD, the phase two clinical trial of AL101 in early Alzheimer's disease. Furthermore, in February 2024, the FDA granted breakthrough therapy designation to latosinamab for FTD-GRN. marking another significant achievement. It is worth noting that although FTD is a complex disease clinically, we have developed a straightforward approach to correcting progranuling deficiency, the underlying cause of the disease. 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 follow-on financing, which Mark will touch on further. Later in this call, Sarah will provide insight in our early research and development efforts, including Alecto's brain carrier technology platform. Our commitment to addressing older 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. This year, we'll continue to focus on delivering and translating our progress into meaningful impact. An important event will be the anticipated data readout from Invoke 2, Phase 2 trial of L002 in the first 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 all the generative disease research, reflecting our firm belief in immunoneurology, in the immunoneurology potential. With that, I will turn it over to Gary to talk about our goals and expectations for our clinical development program. Gary?
spk15: Thank you, Arnon. I'll begin with our AL002 program. the most advanced TREM2 program in clinical development for Alzheimer's disease. 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 microglial signaling pathways, which increase microglial perforation, survival, and function. enhancing the effectiveness of microglia to protect the brain against insults, including age-related neurodegenerative disease. We completed our phase one 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 INVOG2 phase 2b study of AL002 is a randomized double-blind placebo-controlled common closed design study of up to 96 weeks of treatment with AL002, in which 381 participants with early Alzheimer's disease were randomized. The study includes three doses of AL002 that demonstrated robust target engagement and increased microglial signaling in phase one. INVOTE2 completed enrollment ahead of schedule in September of last year. The primary clinical outcome measure for this study is the CDR sum of boxes. We're 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 IADRAS. 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 tau PET. And we'll also have biomarkers of astrogliosis, neuroinflammation, synaptic health, and neurodegeneration. 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 blind at the treatment assignment 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 INFO2 trial have had treatment emergent MRI findings that resemble the amyloid-regulated imaging abnormality for ARIA that has been observed with anti-amyloid therapies. 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. In the current trial population, that includes APOE4 heterozygous and APOE4 non-carriers, analysis of the still-blinded 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 dosed. An independent data monitoring committee reviews data from this trial regularly and continues to recommend that the trial proceed. Our goals for INVOK2 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 TRIM2 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 on the brain. This includes maintaining synaptic connections, supporting astrocyte and oligodendrocyte function, preserving the blood-brain barrier and vasculature, and upholding immune tolerance. Thus, our expectation is that the restoration of microglial 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 hypothesized that by the end of development, AL002 may ultimately display stronger efficacy and 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 therapies. 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 treatment of benefits of AL002 may manifest differently from what we have seen in the anti-amyloid antibody trials. For example, with regard to biomarker responses, lowering cerebral amyloid PET signal to the 20 to 30 centeloid 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. And thus, AL002 has potential to benefit patients from preclinical Alzheimer's disease through advanced dementia. I'll now turn to latacinimat, our novel first-in-class progranulin-elevating candidate and the most advanced therapeutic and clinical development for the treatment of frontotemporal dementia. You may recall that latacinamab has previously received both orphan drug designations for FTD and fast track designation for FTD granulin from FDA. We are pleased to share that in February, FDA granted latacinamab breakthrough therapy designation for FTD granulin based on our In Front 2 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 endpoint. 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 of the pivotal randomized double-blind placebo-controlled InFRONT3 Phase III clinical trial of latacinamab, randomizing 103 participants with symptomatic FTD granulin and 16 participants who were pre-symptomatic at risk for FTD granulin. Our goal was to enroll 90 to 100 symptomatic participants supported by feedback from FDA and EMA. We are actively progressing the InFRONT3 trial in partnership with GSK, and look forward to the pivotal Phase III data readout following the 96-week treatment period. I'd like to now turn to AL-101, our second product candidate in our progranulin portfolio that we are developing in partnership with GSK. Like latazinamab, AL-101 is a monoclonal antibody that blocks sortillin to elevate progranulin levels. Its 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. Our phase one study in Healthy Volunteers demonstrated that AL101 was well tolerated and increased the granular levels in plasma and CSF in a dose-dependent manner. In August 2023, Elector and GSK received FDA clearance of its IND application for AL101 in the treatment of early Alzheimer's disease. The rationale for treatment of 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 disease. Conversely, in animal models of Alzheimer's disease, elevation of progranulin has been shown to be protective. In February of this year, the first participant was DOST 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. 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 outcome 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. Sarah?
spk07: Thank you, Gary. 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, multidimensional functional validation, and data integration with AI-based analysis. 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 technology. While our late-stage clinical candidates show brain penetration and target engagement, we are developing a proprietary versatile blood-brain 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 the CNS. 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. ABC 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 transparent and CD98 heavy chains, with varying affinity. We have been able to achieve greater than tenfold increase in brain concentrations of multiple carbons and demonstrated deep brain penetration to cell types of interest like neurons and microglia. 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, bispecific formats, complemented by customizable FC adaptations for optimized effective function, half-life, and single-chain configuration. Based on the translatability of preclinical safety and efficacy studies, our technology appears to exhibit a favorable safety profile, even when actively engaging with FC. We look forward to sharing more details about our innovative research portfolio, including our electrobrain carrier technology during a virtual event later this year. I'll now turn it over to Mark to provide an update on our financial results. Mark?
spk16: 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 objectives. We continue to focus on fiscal management and program prioritization, and as of December 31st, 2023, our cash, cash equivalents, and short-term investments totals $548.9 million. Strengthening our financial position, we completed a follow-on financing in January of this year, raising $75 million in gross proceeds. Inclusive of this raise, our cash runway is now through 2026, approximately a full year beyond the expected FTDGRN Pivotal Phase 3 Infront 3 data readout, and approximately two years beyond our TREM 2 Phase 2 Invoke 2 data readout. 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. We appreciate the support of significant new investors as well as participation from our existing shareholders. 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 in 2022. Total general and administrative expenses for the quarter were $14.9 million compared to $15.4 million for the same period in 2022. Total general and administrative expenses for the year were $56.7 million compared to $61 million in 2022. 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. And total anticipated general and administrative expenses are estimated to be between $60 and $70 million. In December, ELECTRA hosted two virtual research and development events discussing our TRIM2 and progranulin 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 presentation section of our website. 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.
spk17: Operator, you may now open the line for questions.
spk08: 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. One moment while we compile the Q&A roster. Our first question today is coming from Yaron Werbin of TD Cal, and your line is open.
spk05: Hi, this is Brendan on for Yaron. Thanks very much for taking the question. 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 Transfarin and CD98. 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 kind of going to go indication by indication basis? And then I guess really on the ADP027 asset that you called out in the press release, Kind of just wondering what drove the decision to target and maybe how applicable that target would be kind of to the broader Parkinson's population. Thanks very much.
spk07: Thanks. I'll just address the question about the blood brain barrier technology and then I'll pass it to Arlen to answer your question on GPNMB. Briefly, 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 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, et cetera. We've got bispecific formats. and customizable FC adaptations that allow us to tweak effective function as well as optimize half-life on the molecule. So our approach currently is to, you know, try both these approaches, targeting approaches, trafficking approaches, both for our late stage programs as well as for our novel targets. Maybe Arnon can share his thoughts on our ADP-027 program that you can. Yes.
spk00: So, yeah, we do think that GPNMB targeting will be applicable for sporadic Parkinson's disease. GPNMB is a lysosomal regulator. It's a risk gene for Parkinson's disease. There are both risk and protective variants. And we developed a drug that mimics and exceeds the protective variants. And we think that sort of lysosomal pathology is a general feature in Parkinson's disease. And GPMNB is interacting with LRRK2. It's 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 for any type of Parkinson's disease.
spk05: All right. Thanks very much.
spk08: Thank you. One moment for the next question. And our next question today will be coming from Paul Matias of .
spk04: Hi, this is Julian on for Paul. Thanks so much for taking our question. I guess on AL002, the TRIM2 program, with the readout expected towards the end of the year, the trials Anticipated to run for about a year, at least at a minimum in terms of follow-up. I guess, what gives you guys confidence that this will be long enough to separate from placebo? And do you anticipate at all that there will be a significant group of patients out to two years? And any other color on how the overall data will be analyzed or shared in a top line would be super helpful. Thank you.
spk15: Yeah, hi, thanks for the question. This is Gary. So the study, as you heard, is a common closed design in which all patients will stay in the trial for up to 96 weeks and then roll over into long-term extension. And that is until the last patient out reaches 48 weeks, at which time all patients will roll over into the long-term extension. And so we will have data, not only will we have data out to 48 weeks on everybody, but we'll also have data out to, 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. 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, do we think this is enough time to see treatment effect? You know, we're looking at treatment effect in this study as Appy and Elector designed the study in order to be a biomarker-rich study that will 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. 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 sub-studies, but also now with the acceleration and validation of phosphatau assays, we'll be looking at P217 and tau aggregates in plasma on all patients. So we feel confident that we are going to, through this totality of this data, be able to determine whether we're slowing the progression of Alzheimer's disease, which is what the original design was intended to do.
spk04: Excellent. Thanks for the color.
spk08: 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.
spk03: Hi. Hi. This is Michael Riad on for Jeff Hung. Thank you for taking our question. For INVOQ, how do you expect levels of soluble TREM2 to look at for patients at baseline with preclinical AD versus maybe a little bit more progressed dementia? Like, does a higher baseline soluble TREM2 level, like, imply higher chances for, like, a pharmacodynamic effect?
spk15: 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 TREM2 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 TREM2 causes internalization of the receptor. And this actually causes a reduction in soluble TREM2 because what we're basically doing is reducing by binding and internalizing receptor, we're lowering the levels of microglial membrane TREM2, which is and that reduces the amount of the cleavage product, soluble TREM2, which is constituently cleaved from TREM2, right? So we will see, as we saw, we intend to see, as we did in phase one, a reduction in soluble TREM2. You know, again, there's different ideas about soluble TREM2 and what its role is. We believe that primarily it's a really a marker of membrane TREM2. And, you know, there's a fair amount of data out there that suggests that soluble TREM2 levels, which, again, are reflecting the amount of TREM2 in the membrane, correlate, you know, as they are higher, they correlate with better outcomes or progression of disease, of Alzheimer's disease, slower progression. conversion from MTI to Alzheimer's disease, slower progression of brain volume loss. So again, but that is a function basically of having greater TREM2 activity, and our antibody increases TREM2 signaling.
spk03: Thank you so much. Really helpful.
spk08: Thank you. One moment for the next question. And our next question will be coming from Pete Stavrapas of Cantor Fitzgerald. Your line is open.
spk14: Hi, Arun and team. Thank you for taking my questions. So first one, you know, I believe that, you know, for the INVOK2 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 to 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, you know, that could suggest that the starting dose is therapeutically active? And if so, you know, what would be, you know, the key biomarker or biomarkers you believe may be informative at that time point?
spk15: Yeah, thanks, Pete. A good question. So you're right. We are, so just to clarify, in the long-term extension, all patients that were unactive, doses in the double-blind will roll over to the same dose and continue in the long-term extension. Those that were originally randomized 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, in some of the anti-amyloid therapeutics, there's been data that suggests that starting at a lower dose and or titrating more slowly than we did in this double-blind study could be mitigated. So that's one advantage. We do believe that this slow titration, though, is actually going to help us in another way, not only to learn about mitigation for ARIA, but also help us to, in a sense, it will, 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 to look for not only for safety, but also to look for treatment effects on biomarkers, and most importantly, on clinical outcome measures. So, for example, with the common closed design, some of the patients will have a year, only a year of data, follow-up data on clinical outcomes, but in the long-term extension, which would really essentially be a randomized start design, we'll be able to look for differences between the original placebo group and the active dose groups in the long-term extension. We'll be able to look at those clinical outcome assessments and differences between the placebo and actives in that long-term extension.
spk14: All right. Thank you for that. And, you know, one question on the phase two for AL101, you know, originally initiated with GSK. You know, just... Looking at the study design, I see that there are two undisclosed doses being evaluated. How did you select those doses, if you can tell us? Was it based on a certain level of PRGN increase in the phase one? Are you trying to keep it above a certain threshold or below a certain level?
spk15: Sarah, I'll start. Maybe, Sarah, if you want to chime in on the PK here behind it. Yeah, these, so we have two doses. We have a maximal dose that gives us maximal, you know, elevations of progranulin, and we also chose a somewhat lower dose, and those, the, 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
spk07: Thanks, Gary. Agreed, Pete. We haven't disclosed their actual doses or the selection, but mostly 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. We haven't really shared the exact doses or the exact criteria for the selection of the dose.
spk14: Okay. Thank you for taking my questions.
spk08: 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.
spk18: Hey, good afternoon. 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?
spk15: 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 that there are also a number of other beneficial effects of microglia that they do in normal maintenance to preserve brain health, reduce vulnerability of the brain to to insults, including age-related neurodegenerative diseases. And I think we mentioned those a couple of times in the presentation. 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 mechanisms, downstream mechanisms of healthy, you know, that are in play because of healthy microglia, that there are a number of things we can measure, and we're going to be measuring in the study, including the typical Alzheimer's biomarkers that we mentioned, A, beta, and tau, both in plasma and with PET scans. We'll also be measuring astrocyte, you know, effects on astrocytes and synapses and and oligodendrocyte function, et cetera. I think the totality, really what a 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, 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 AD. 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 microtubule binding region assay. I want to emphasize, you know, this study is powered for clinical effect of about 40%. That's a big effect. So, you know, we may or we may not see a clinically significant effect of that size in this relatively small Phase II 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.
spk18: Got it. That's really helpful. Thanks.
spk08: Thank you. Thanks, Greg. One moment. And our next question will be coming from Corinne Johnson of Goldman Sachs. Your line is open.
spk07: Hi, this is , just one for us. Could you please share what's embedded in the CASH runway guidance with respect to clinical activities, more so beyond the near-term clinical events?
spk16: Yeah, thanks for the question. So I think the question was around what's included in the CASH runway guidance. 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 three data and also allows us to accelerate our investment in our blood-brain barrier technology platform and also our proprietary earlier stage pipeline. Importantly, it's conservative in the sense that we're not including any milestones from partners, including the a 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, also continued spend on that program for the extension study, and spend on the FTD-GRN Phase 3, and also spend on the recently commenced AL-101 Phase 2 for Alzheimer's disease. Those are the major components in addition to, you know, continuing to progress our blood-brain barrier platform in early pipeline.
spk09: Understood. Thank you. Thanks for the question. Thank you. One moment for the next question.
spk08: And our next question is coming from Carter Gould of Barclays. Your line is open.
spk11: This is Leon for Carter. Thanks for taking my question. So we have two on Invoke 02. So at this point, do you have alignment or understanding with Abby on what a potentially good profile could look like on the readout? In terms of your update on achieving 90% enrollment in the OLE from InVocal 2, 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 implication of getting 90% enrollment in the OLE, 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.
spk15: Yeah, well, to the latter question, just that that's 90% of those that were eligible to roll over out of the 96-B common closed design study. And, you know, I mean, I think that we believe that reflects, you know, an interest in patients to continue. You know, there are increasingly other options, like they could start taking lacanumab. But most, you know, if you hear, you know, 90% or so are rolling over and staying in the long-term extension, which we, you know, interpret positively in terms of tolerability and potentially, you know, other effects of the drug. But we can't, we really can't. know uh speculate on at this point um 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 you're asking you're asking oh i know i remember now about the readout right so yeah so um sorry i'm sorry i just had a blank out there so yeah so as i mentioned we've been aligned with that be really from the start on on how we design this this study that we're really looking at the totality of the data to tell us whether we're slowing the progression of Alzheimer's disease to make a decision on what happens next with this compound and whether it progresses. So that includes, as I said, clinical outcome measures, and it includes some functional measures, and it includes a lot of biomarkers. 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 progression.
spk17: Roger, thank you. I hope that answers your question. Yep.
spk08: Thank you. One moment for the next question. And our next question will be coming from our mentor of William Blair. Your line is open.
spk01: Hey, just a couple on Invoke2. Are there any sort of material differences that you're seeing in the ARIA incidence rates between the double-blind portion of Invoke2 and the long-term open label extension. I would assume that REO goes up if you're having placebo switch to active drug in that arm. That's the first question. The second one is 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.
spk15: Yeah, thank you. To the second question, we will have the capability of doing that post, 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, you know, in order to see whether there are differential effects based on baseline tau. not the baseline teleopathy. Yep. And I guess I should do this in the other direction. And your first question was, oh, around the ARIA signal. Yep. So we've shared this data, the imaging, the MRIs, the MRIs themselves, the clinical vignettes, these patients, and truly this looks indistinguishable from the area that has been described with anti-amyloid antibodies with, 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, you know, the time to onset and resolution, the relatedness to number of APOE4 alleles, the MRI features themselves, and the clinical manifestation. So it really, we really, you know, we don't see any differences, and we've shown it to number of uh of the area experts who have also said that this is really indistinguishable and i don't think we see any difference between the domain study and the extension study either miles okay so no difference from the 19 to 23 percent that you reported compared to your most yeah no sorry sorry we you know we're blinded to to to who's who in the study um but um you know so far so far we have seen very little area in in the uh uh in the uh long-term extension so uh that yeah earlier days with with the extension study miles so you know to try to draw inferences from those percentages would be you know difficult cool thanks for the questions
spk08: Thank you. One moment for the next question. And our next question is coming from Nina Riccio Garg of Deutsche Bank. Your line is open.
spk06: Hi, it's Avi Novak on the line for Nina. Thank you for taking our question. So on the ABCA technology, can you discuss how your transfer and approach differs from other transfer and base delivery platforms and then Also on INVOK2, given what you know about the ALOO2 mechanism, which biomarkers do you see as being most likely to be correlated with improvement on CDR sum of boxes or any other point-to-point points?
spk07: Thanks. I can start with the ABC technology, and then Gary can address your second question. So in terms of our BBB approach, it employs a versatile brain barrier carrier technology which 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 is customizable. based on the sort of the requirements of therapeutic affinity, valency, and format, and we can match that to a variety of cargoes. We use bispecific 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 effective function as well as half-life. 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 EPCIE engagement. And we will be, by the way, we will have a webinar So 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 at that time.
spk09: And I'll pass it to Gary. What was that question? I'm sorry.
spk06: I didn't hear you. 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 boxes or more generally on the cloud?
spk15: Sure, sure. Well, again, that would be the biomarkers of Alzheimer's pathophysiology. Most importantly, I think the tau biomarkers. Both will be, we will have TAO-PET, which will be a TAO-PET sub-study, but we will also have plasma biomarkers on everybody in this study, the P217, and hopefully microtubule binding region assay as well. So this will, you know, this will give us a, that's really the TAO biomarkers are the ones that correlate most closely with clinical outcomes. And really can be seen, I think, as, you know, sort of a, you know, summing up the effects, all these, you know, hypothetical effects of benefits of healthy microglia on slowing the disease progression.
spk17: Great. Thank you, and congrats on the quarter. Thank you.
spk08: Thank you. One moment for the next question. And our next question is coming from Thomas Schrader of BTIG. Your line is open.
spk02: Hey, good afternoon. This is Tom. I'm for Tom. So for the ongoing Phase II Progress AD study, is there a reason to perhaps stratify these patients based on baseline programming levels for the possible substance analysis in the future?
spk18: Thank you.
spk15: Yeah, thanks for the question. We did not do, we were not doing that, and that's because it, you know, part of the evidence in favor or in support of this mechanism is that even modest, that mutations that cause even very modest effects in progranular 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 progranulin levels. There's also animal data, which maybe Arnon may want to speak more to, that shows that in various animal models of Alzheimer's disease that just elevating progranulin itself is protective against disease progression.
spk09: Great, thank you.
spk08: One moment for the next question. And our next question will be coming from Ananda Bush of H.D. Wainwright. Your line is open.
spk13: Hey, hi, congrats on the quarter. You know, given the biology of TREM2 and from your own ARIA data, I think, you know, there's little doubt that experts, you know, believe, there's little doubt on the fact that the TREM2 might be involved in plaque removal. However, one question which I have, and, you know, that's based on Lekanema 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, you know, P tau 217, You know, do the MRI data, you know, the tau PET, the tau PET ebita data, along with the plasma tau biomarkers, puts you into a position where you can negotiate an accelerated approval pathway, which strategically might be very similar to the CalSODI, you know, CalSODI approach? So that's the question. Thank you.
spk15: Yeah, thank you. So if I understand your question, you're wondering whether based on changes or treatment-related changes on tau PET or on tau biomarkers, could that be the basis of an accelerated approval approach?
spk13: Right. You know, if there is a clear sign that there is, you know, a remarkable change in the plasma tau biomarker based on the plaque removal, is there a potential for accelerated approval pathway similar to CalSODI approach?
spk15: Yeah. I would never say no. 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 And again, I think a way of going at this differently. That's not the original intention of this trial, 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.
spk17: Sorry. Thank you.
spk09: Thank you.
spk08: And our final question for today will be coming from Greg Sivanevi of Mitsuhu Securities. Your line is open.
spk10: Greg, are you there?
spk09: Your line is open.
spk08: I would now like to go ahead and turn the call back over to Mark Grasso for final remarks.
spk16: 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 Cowen's 44th Annual Healthcare Conference on March 5th in Boston, Laring's 2024 Global BioPharma Conference on March 12th in Miami, Barclays Global Healthcare Conference on March 13th in Miami, and Steeples CNS Days March 19th. Thank you again for your time and attention. We'll now conclude today's call.
spk08: This concludes today's conference call. You may all disconnect.
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