Alector Q4 2023 Earnings Call Transcript

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Provided by Quartr
February 27, 2024

There are 13 speakers on the call.

Operator

Good day and thank you for standing by. Welcome to Elekta's Q4 2023 Earnings Conference Call. At this time, all participants are in a listen only mode. After the speakers' presentation, there will be a question and answer 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.

Operator

Please go ahead.

Speaker 1

Thank you, operator, and hello, everyone. Earlier this afternoon, we released our financial results for the Q4 full year 2023. The press release is available on our website at www.electra.com. And our 10 ks was filed with the Securities and Exchange Commission this afternoon. Joining me on the call today are Doctor.

Speaker 1

Arnon Rosenthal, Co Founder and CEO Doctor. Sarah Kankari Mitra, President and Head of Research and Development Doctor. Gary Romano, Chief Medical Officer and Doctor. Mark Grasso, Chief Financial Officer. After our formal remarks, we'll open the call for Q and A.

Speaker 1

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?

Speaker 2

Thank you, Katie. Good afternoon, everyone, and thank you for joining Elektor for our Q4 and full year 2023 financial results conference call. I'll begin by highlighting the broad mechanistic potential of our immuno neurology 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 on our 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.

Speaker 2

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 immuno neurology 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'm pleased to highlight that 2023 was marked by successful clinical execution and clarity around timelines for our advanced clinical development programs. We achieved significant milestone in our late stage program, reinforcing electrodes standing as a pioneer in immuno neurology. Importantly, we completed trial enrollment for our 2 lead programs.

Speaker 2

This include the pivotal INFRON3 Phase 3 trial of our pro granularly elevating candidate latuzinumab in front of the triple dementia with pro granularly gene mutation or STD GRN and in VOQ2 Phase 2 trial of our TRAM2 candidate AL002 in early Alzheimer's disease. In partnership with GSK, we also recently dosed the 1st participant in progress AD, the Phase 2 clinical trial of AL101 in early Alzheimer's disease. Furthermore, in February 2024, the FDA granted breakthrough therapy designation to ratocinumab for FTDGRN, marking another significant achievement. It is worth noting that although FTD is a complex disease clinically, we have developed a straightforward approach to correcting pro granularly deficiency, the underlining cause of the disease. Collectively, these advancements move us closer to potential meaningful data readout this year and next.

Speaker 2

In January, we also further strengthened our balance sheet with the completion of $75,000,000 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 neurodegeneration 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 translation translating our progress into meaningful impact. An important event will be the anticipated data readout from INVOK2 Phase 2 trial of L002 in the Q4.

Speaker 2

This will potentially be a major step forward in elucidating our immuno neurology hypothesis. Together with the support from our partners, we are committed to advancing neurodegenerative disease research, reflecting our firm belief in immuno neurology and the immuno neurology potential. With that, I will turn it over to Gary to talk about our goals and expectations for our clinical development program. Gary?

Speaker 3

Thank you, Arnon. I'll begin with our AL-two program, the most advanced TREM-two program in clinical development for Alzheimer's disease. AL-two is a novel investigational humanized monoclonal antibody that binds to and activates TREN2, a key microglial receptor that senses pathological changes in the brain. Binding of AL002 to the TRM2 receptor triggers microglial signaling pathways, which increase microglial proliferation, survival and function, enhancing the effectiveness of microglia to protect the brain against insults, including age related neurodegenerative disease. We completed our Phase 1 trial of AL-two in healthy volunteers, which demonstrated both dose dependent target engagement and activation of microglia.

Speaker 3

In the trial, AL-two is also shown to be well tolerated. Our ongoing INVOQ-two Phase 2b study of AL-two is a randomized double blind placebo controlled common closed design study of up to 96 weeks of treatment with AL-two in which 381 participants with early Alzheimer's disease were randomized. The study includes 3 doses of AL-two that demonstrated robust target engagement and increased microglial signaling in Phase 1. INVO2 completed enrollment ahead of schedule in September of last year. The primary clinical outcome measure for this study is the CDR soma boxes.

Speaker 3

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 IADRIS. 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 abeta 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 are in the study for up to 96 weeks.

Speaker 3

We also have a long term extension where we remain blinded to 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 INVOQ-two trial have had treatment emergent MRI findings that resemble the amyloid related 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, incidents, 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 STIL binded data shows 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.

Speaker 3

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 INVOQ-two trial and for AL-two 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 TRPM2 agonism may be to increase the clearance in misfolded proteins, including amyloid, we expect AL-two to 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.

Speaker 3

Thus, our expectation is that the restoration of microglial function by AL-two will reduce the brain's vulnerability to neurodegenerative disease and that the INVOQ-two 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, AL-two may ultimately display stronger efficacy than current therapies that target individual misfolded proteins. Through its novel and complementary mechanism of action, we expect AL-two to be effective either as a standalone therapy or in combination with anti amyloid therapies. Given that agonism of TREM-two has the potential to reduce the brain's vulnerability to neurodegenerative disease through these multiple downstream mechanisms, we believe that treatment of benefits of AL-two 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 seniloid 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.

Speaker 3

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 be limited to specific pathophysiological stages of disease. And thus AL-two has potential to benefit patients from preclinical Alzheimer's disease through advanced dementia. I'll now turn to latasinumab, our novel first in class pro granular and elevating candidate and the most advanced therapeutic and clinical development for the treatment of frontal temporal dementia. You may recall that latasinumab has previously received both orphan drug designation for FTD and fast track designation for FTD granuline from FDA.

Speaker 3

We are pleased to share that in February FDA granted latasintimab breakthrough therapy designation for FTD granulan based on our INFRONT2 Phase 2 clinical trial data. FDA's breakthrough therapy designation is granted to expedite the development and review of drugs that are intended to treat a serious condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint. With this designation, we look forward to continued productive conversations with the FDA, recognizing the unmet need for people living with FTD granuline, 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 3 clinical trial of latasintimab, randomizing 103 participants with symptomatic FTD granuline and 16 participants who were pre symptomatic at risk for FTD granuline. Our goal was to enroll 90 to 100 symptomatic participants supported by feedback from FDA and EMA.

Speaker 3

We are actively progressing the INFRIN3 trial in partnership with GSK and look forward to the pivotal Phase 3 data readout following the 96 week treatment period. I'd like to now turn to AL-one hundred and one, our 2nd product candidate in our progranulin portfolio that we are developing in partnership with GSK. Like latuzinumab, AL101 is a monoclonal antibody that blocks tortillin to elevate prognylin 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 1 study in healthy volunteers demonstrated that AL-one hundred and one was well tolerated and increased progranin levels in plasma and CSF in a dose dependent manner.

Speaker 3

In August 2023, Elektor and TSK received FDA clearance of its IND application for AL-one hundred and one in the treatment of early Alzheimer's disease. The rationale for treatment of Alzheimer's disease is that genetic variance that results 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 protected. In February of this year, the first participant was dosed 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 AL101 enrolling approximately 282 patients with early Alzheimer's disease at multiple sites globally.

Speaker 3

The 36 week study is designed to assess the safety and efficacy of 2 dose levels of AL-one hundred and one compared to placebo. Participants are randomized to 1 to 3 dose tubes receiving AL101 or placebo intravenously. The primary endpoint of the study is disease progression as measured by the CDR somber boxes. The trial also employs other clinical and functional outcomes assessments and biomarkers. We look forward to sharing additional information on progress AD as the trial advances.

Speaker 3

With that overview, I'll now turn the call over to Sarah to provide an update on our early research pipeline. Sarah?

Operator

Thank you, Gary.

Speaker 4

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, 1st in class immuno neurology drug candidates.

Speaker 4

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 electro brain 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 transferrin and CD98 heavy chain with varying affinity. We have been able to achieve greater than 10 fold increase in vein concentrations of multiple carbons and demonstrated deep brain penetration to cell types of interest like neurons and microglia.

Speaker 4

The modular nature of this technology allows the affinity, valency and format of the final therapeutic to be harmonized with the mechanism of action and sell that 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 efficacy. We look forward to sharing more details about our innovative research portfolio, including our electro brain carrier technology during a virtual event later this year.

Speaker 4

I'll now turn it over to Mark to provide an update on our financial results. Mark?

Speaker 5

Thank you, Sarah. As summarized in our Q4 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 31, 2023, our cash, cash equivalents and short term investments totaled $548,900,000 Strengthening our financial position, we completed a follow on financing in January of this year raising $75,000,000 in gross proceeds. Inclusive of this raise, our cash runway is now through 2026 approximately a full year beyond the expected FTD Gearend pivotal Phase 3 INFRONT 3 data readout and approximately 2 years beyond our TRM-two Phase 2 INVOQ-two 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 Electra Brain Carrier technology platform.

Speaker 5

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 Q4 was $15,200,000 compared to $14,400,000 for the same period in 2022. Collaboration revenue for the year was $97,100,000 compared to $133,600,000 in 2022. Total research and development expenses for the 4th quarter were $47,700,000 compared to $54,500,000 for the same period in 2022.

Speaker 5

Total research and development expenses for the year were $192,100,000 compared to $210,400,000 in 2022. Total general and administrative expenses for the quarter were $14,900,000 compared to $15,400,000 for the same period in 2022. Total, general and administrative expenses for the year were $56,700,000 compared to $61,000,000 in 2022. For 2024, we estimate our collaboration revenue to be between $60,000,000 $70,000,000 Our anticipated total research and development expenses are estimated to be between $210,000,000 $230,000,000 total anticipated general and administrative expenses are estimated to be between $60,000,000 $70,000,000 In December, Elektra hosted 2 virtual research and development events discussing our TREM2 and Prograngulin programs in detail. The events included presentations from leading scientific and clinical experts.

Speaker 5

We encourage those who didn't have an opportunity to participate in the live events to watch the replays located under the Investor Events and Presentations section of our website. We remain focused on advancing our novel portfolio and electro brain care technology to treat neurodegenerative diseases. We look forward to providing additional updates as we advance our work. That concludes our prepared comments for today's call. Operator, you may now open the line for questions.

Operator

Thank Our first question today is coming from Yaron Werbin of TD Cowen. Your line is open.

Speaker 6

Hi, this is Brendan on for Yaron. Thanks very much for taking the question. Just a couple of 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 transferrin and CD98.

Speaker 6

Are you kind of at this point planning to kind of choose 1 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 ADP-twenty seven asset that you called out in the press release, Just wondering what drove the decision to target GPN and maybe how applicable that target would be to the broader Parkinson's population? Thanks very much.

Speaker 4

Thanks. I'll just address the question about the blood brain barrier technology and then I'll pass it to Arnan 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 2nd generation efforts for our current late stage programs as well as our new novel sort of target molecules in research and certainly do not have any intent initially to choose one over the other. We will depending on the best approach for each target and each molecule.

Speaker 4

Again, we are using very adaptable technology, which allows us to customize for therapeutic affinity, valency, etcetera. We've got, bispecific formats and customizable Fc adaptations that allow us to tweak effective function as well as optimize half life on the both for our late stage programs as well as for our novel targets. And maybe Arun can share his thoughts on our ADP-twenty seven program that can.

Speaker 2

Yes. So yes, we do think that GPN MB targeting will be applicable for sporadic Parkinson's disease. GPRMB is a lysosomal regulator or it's a risk gene for Parkinson's disease. There are both risk and protective variants and we developed a drug that mimic and exceed the protective variants and we think that sort of lysosomal pathology is a general feature in Parkinson's disease and GPMNB is interacting with LARK2, is interacting with GCAS to other risk genes for Parkinson's disease. It's not regulated in multiple types of sporadic PD.

Speaker 2

So we do think that it will be applicable for any type of Parkinson's disease.

Speaker 6

All right. Thanks very much.

Operator

Thank you. One moment for the next question. And our next question today will be coming from Paul Matteis of Stifel.

Speaker 6

Hi, this is Julian on for Paul. Thanks so much for taking our question. I guess on AL-two, the TREN-two program, with the readout expected towards the end of the year, the trials anticipated to run for about a year at least for at least at a minimum in terms of follow-up. I guess what gives you guys confidence that this will be long enough to separate from placebo? And do you anticipate at all that there will be

Speaker 3

So the study, as you heard, is a common close design in which all patients will stay in the trial for up to 96 weeks and then roll over into long term extension 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 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.

Speaker 3

You asked a question about, do we think this is enough time to see treatment effect? We're looking at treatment effect in this study as AbbVie and Elektor 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 in validation of phosphatau assays, we'll be looking at P2 17 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 individual design was intended to do.

Speaker 6

Excellent. Thanks for the color.

Operator

Thank you. One moment for the next question. And our next question will be coming from Jeffrey Huang of Morgan Stanley. Your line is open.

Speaker 6

Hi. This is Michael Riad on for Jeff Hong. Thank you for taking our question. For Invoke, how do you

Speaker 7

expect levels of soluble TREM-two to

Speaker 6

look at for patients at baseline with preclinical ID versus maybe a little bit more progressed dementia? Like, does a higher baseline soluble TREN2 level like imply higher chances for like a pharmacodynamic effect?

Speaker 3

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 are not enrolling, for example, just those with genetic variants like the R47H variant. 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 TRAM2 causes internalization of the receptor.

Speaker 3

And this actually causes a reduction in soluble TRM2 because what we're basically doing is reducing by binding and internalizing receptor, we're lowering the levels of microglial membrane TRM2, which and that reduces the amount of the cleavage product, soluble CHEM-two, which is constitutally cleaved from CHEM-two, right. So we plan we will see as we saw we intend to see as we did in Phase 1, a reduction in soluble CHEM-two. Again, there's different ideas about soluble TREM2 and what its role is. We believe that primarily it's really a marker of membrane TREM2. And there's a fair amount of data out there that suggests that soluble TREM2 levels, which are again are reflecting the amount of TRM2 in the membrane correlate as they are higher, they correlate with better outcomes or progression of disease, of Alzheimer's disease, slower conversion from MCI to Alzheimer's disease, slower progression of brain volume loss.

Speaker 3

So again, but that is a function basically of having greater TRM2 activity and our antibody increases TRM2 signaling.

Speaker 6

Thank you so much. Really helpful.

Operator

Thank you. One moment for the next question. And our next question will be coming from Pete Stavropoulos of Cantor Fitzgerald. Your line is open.

Speaker 8

Hi, Arun and team. Thank you for taking my questions. So first one, I believe that for the INVOQ-two study, the placebo rolls over. You will start you will be starting them at a lower dose than those in the original randomized to active arm and then titrating them upwards. Can you just discuss the timeline for the titration?

Speaker 8

And will you be able to capture any data points, especially biomarker wise that could suggest that the starting dose is therapeutically active? And if so, what would be the key biomarker or biomarkers you believe may be informative at that time point?

Speaker 3

Yes. Thanks, Pete. A good question. So you're right. We are so just to clarify, in the long term extension, all patients that were on active doses in the double blind will roll over to the same dose and continue in the long term extension.

Speaker 3

Those that were originally randomized placebo will be titrated up started on active beginning with a tight with a at a lower dose, that's right, 6 milligrams per kilogram and increase and they will be dose escalated every 2 months. And one reason for doing this is to learn more about the potential mitigations for the area like signal that we're seeing. As you know, and some of the anti amyloid therapeutics has 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 and 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.

Speaker 3

This will give us an opportunity to continue to follow patients beyond the double blind into the long term extension to look for not only for safety, but also to look for treatment effects on biomarkers and most importantly on clinical outcome measures. So for example, with the common close design, some of the patients will have a year only a year of data, a follow-up data on clinical outcomes. But in the long term extension, this 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 from the between the placebo and actives in that long term extension.

Speaker 8

All right. Thank you for that. One question on the Phase II for AL-one hundred and one, was originally initiated with GSK. Just looking at the study design, I see that there are 2 undisclosed doses being evaluated. How did you select those doses?

Speaker 8

If you can tell us, was it based on a certain level of PRGN increase in the Phase 1? Are you trying to keep it above a certain threshold or below a certain level?

Speaker 3

Sarah, I'll start. Maybe Sarah, if you want to chime in on the PK here behind it. Yes, these so we have 2 doses. We have a maximal dose that gives us maximal 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.

Speaker 3

So I'm going to have to defer to Mark or Sarah as to whether we're

Speaker 4

Thanks Gary. Yes, 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 1 single and multiple ascending dose studies and based on programmable levels of course. So it was the elevation of programmable in plasma and CSF that was modeled and based on this, the 2 doses were selected. We haven't really shared the exact doses or the exact criteria for the selection of the dose.

Speaker 8

Okay. Thank you for taking my questions.

Operator

Thank you. One moment for the next question. The next question will be coming from Greg Harrison of Bank of America. Your line is

Speaker 9

open. Hey, good afternoon. Thanks for taking the question. What endpoints that you'll report from the INVOOC-two trial do you think will be key to understanding the benefit of ALO-two's various mechanisms beyond amyloid reduction and potentially showing differentiation versus anti amyloid antibodies?

Speaker 3

Yes. Thank you for that question, Greg. So 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 includes may include enhanced clearance in 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 insults, including age related neurodegenerative diseases. And I think we mentioned those a couple of times in the presentation.

Speaker 3

So the in this study, therefore, we are and again, this is a novel mechanism, and we think that it's important to realize that the that through these various downstream mechanisms of healthy 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 outside the typical Alzheimer's biomarkers that we mentioned, A beta and tau, both in plasma and on PET scans. We'll also be measuring, effects on astrocytes, synapses and oligodendocyte function, etcetera. 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.

Speaker 3

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 correlate most closely with disease progression in NAD. And so we'll be looking at the clinical outcome measures, we'll be looking at the Alzheimer's biomarkers, particularly, for example, plasma P-two seventeen and also looking at tau aggregates with other tau phosphoassays like the microcebo binding region assay. I want to emphasize the study is powered for clinical effect of about 40%. That's a big effect.

Speaker 3

So we may or we may not see a clinically significant effect of that size in this relatively small Phase 2 study. But again, the original design was intended not to be have a decision made on the primary clinical endpoint, but on the totality of the data, particularly the biomarker data that I mentioned.

Speaker 9

Got it. That's really helpful. Thanks.

Operator

Thank you.

Speaker 5

Thanks, Greg.

Operator

One moment. And our next question will be coming from Corrine Johnson of Goldman Sachs. Your line is open.

Speaker 4

Hi, this is Sanuk on for Corinne. 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?

Speaker 5

Yes. Thanks for the question. 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 and that's 2 years post the anticipated TRM-two data and also approximately full year beyond the anticipated FTDGRN Phase 3 data and also allows us to accelerate our investment in our blood brain barrier technology platform and also our prior to early stage pipeline. Importantly, it's conservative in the sense that we're not including any milestones from partners including the potential significant opt in from AbbVie at the end of the completion of the Phase 2.

Speaker 5

And it does include a full spend on 2 through the Phase 2 completion, also continued spend on that program for the extension study and spend on the FTDGRN Phase 3 and also spend on the recently commenced AL-one hundred and one Phase II for Alzheimer's disease. Those are the major components in addition to continuing to progress our BloodRay Bearer platform and earlier pipeline.

Speaker 4

Understood. Thank you.

Speaker 5

Thanks for the question.

Operator

Thank you. One moment for the next question. And our next question is coming from Carter Gould of Barclays. Your line is open.

Speaker 10

Hi, this is Leon on for Carter. Thanks for taking my question. So we have 2 on Invoke O2. So at this point, do you have alignment or understanding with AbbVie on what a potentially good profile could look like on the readout? And in terms of your update on achieving 90% enrollment in the OLE from Invoca 2.

Speaker 10

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 like to highlight in terms of what this could tell you about the safety and tolerability profile? Thank you.

Speaker 3

Yes. Well, to the latter question, just that that's 90% of those that were eligible to roll over out of the 96B common close design study. And I mean, I think that we believe that reflects an interest in patients to continue. There are increasingly other options like they could start taking lutinumab. But most as you see as you hear, 90% or so are rolling over and staying in the long term extension, which we interpret positively in terms of tolerability and potentially other effects of the drug.

Speaker 3

But we can't we really can't speculate on at this point. I'm blanking on your first question. I'm sorry. Can you just remind me at the beginning? I'm sure I'll remember it.

Speaker 3

You're asking, you're asking, oh, I know I remember now about the readout, right. So, sorry, sorry, I just had a blank out there. So yes, so as I mentioned, we've been aligned with that really from the start on how we design 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, which 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. So and particularly, 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.

Speaker 2

Got it.

Speaker 3

Thank you. I hope that answers your question.

Speaker 5

Yeah.

Operator

Thank you. One moment for the next question. And our next question will be coming from Myles Winter of William Blair. Your line is open.

Speaker 11

Hi. Just a couple on IMVOQ2. Are there any sort of material differences that you're seeing in the ARIA incidence rates between the double blind portion of IMVOQ2 and the long term open label extension, I would assume that ARIA goes up if you're having placebo switch to active drug in that arm. That's the first question. The second one is you're measuring tau in all of those patients.

Speaker 11

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.

Speaker 3

Yes. Thank you. To the second question, we will have the capability of doing that post we didn't we didn't stratify the part the study based on tau, but we will be able to look with plasma p Tau measures in order to see whether there are differential effects based on baseline tau not the baseline tauopathy. And I guess, I should be in some other direction. And your first question was around the ARIA signal.

Speaker 3

Yes. So we've shown we've shared this data, the imaging, the MRI the MRIs themselves, the clinical vignettes, these patients and surely 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 time to onset and resolution, the relatedness to number of A2E4 alleles, the MRI features themselves and the clinical manifestation. So it really we really we don't see any differences and we've shown it to a number of the ARIA experts who have also said that this is really indistinguishable.

Speaker 5

And I don't think we see any difference between the main study and the extension study either Miles to your question.

Speaker 11

Okay. So no difference from the 19% to 23% that you reported at AIC compared to your most?

Speaker 3

Yes. No, sorry, sorry. We're blinded to who's who in the study. But so far we have seen very little area in the long term extension. So that Yes, I think also

Speaker 5

earlier days with the extension study mile. So to try to draw inferences from those percentages would be difficult.

Speaker 11

Cool. Thanks for the questions.

Speaker 6

Yes.

Operator

Thank you. One moment for the next question. And our next question is coming from Nina Ricchiogarg of Deutsche Bank. Your line is open.

Speaker 12

Hi, it's Avi Novak on the line for Nina. Thank you for taking our questions. So on the ABC technology, can you discuss how your transferrin approach differs from other transferrin based delivery platforms? And then also on Invoke II, given what you know about the AL002 mechanism, which biomarkers do you see as being most likely to be correlated with improvement on CDR somaVos or any other pinpoint points? Thanks.

Speaker 4

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 blood 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 10 fold increases in brain concentrations utilizing these multiple cargoes. I think what's unique about our technology is that it is an adaptable technology and it's sort of modular and it's customizable based on the 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.

Speaker 4

As we said in the call, our safety and efficacy studies in non human primates thus far suggest a favorable safety and efficacy profile even when we have Fc engagements. And we will be by the way, we will have a webinar, so I don't the date is 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. And I'll pass it to Gary.

Speaker 3

What was that question? I'm sorry. I didn't hear it.

Speaker 4

Yes. So just

Speaker 12

for IMVOQ2 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 Sure.

Speaker 3

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 tau PET, which will be a Tau PET substudy, but we will also have plasma biomarkers on everybody in the study, so P-two seventeen and hopefully microtubule binding region assay as well. So this will give us a that's the really the tau biomarkers are the ones that correlate most closely with clinical outcomes and really can be seen, I think, as sort of a summing up the effects, all these hypothetical effects of healthy benefits of healthy microglia on slowing the disease progression.

Speaker 12

Great. Thank you and congrats on the quarter.

Speaker 5

Thank you.

Operator

Thank you. One moment for the next question. And our next question is coming from Thomas Schrier of BTRG. Your line is open.

Speaker 9

Hey, good afternoon. This is Tom on for Tom. So for the ongoing Phase 2 progress AD study, is there a reason to perhaps stratify these patients based on baseline programming levels for a possible subset analysis in the future? Thank you.

Speaker 3

Yes. Thanks for the question. We did not do we're not doing that and that's because it in the 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 progranulin levels increase the risk of Alzheimer's disease. And so we didn't believe that it would be necessary. And our hypothesis is that this would be effective in slowing disease progression regardless of your baseline progranulin levels.

Speaker 3

There's also animal data which we may want to speak more to that shows that in various animal models of Alzheimer's disease that just elevating pro granular in itself is protective against disease progression.

Speaker 9

Great. Thank you.

Operator

One moment for the next question. And our next question will be coming from Ananda Ghosh of H. C. Wainwright. Your line is open.

Speaker 7

Hey, hi. Congrats on the quarter. Given the biology of TREN2 and from your own ARIA data, I think there's little doubt that experts believe there's little doubt on the fact that the TRM2 might be involved in plaque removal. However, one question which I have and that's based on lekanimab and tonanumab and also a lot of questions on tau biomarkers today here. Given the data from those two trials and

Speaker 3

the recent

Speaker 7

publication validating plasma p Tau217, Do the MRI the tau PET A beta 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 approach? So that's the question. Thank you.

Speaker 3

Yes. Thank you. So if I understand your question, you're wondering whether based on changes or just or treatment related changes on tau PET or on tau biomarkers, could that be the basis of an accelerated approval approach?

Speaker 7

Right. If there is a clear sign that there is a remarkable change in the plasma biomarker based on the plaque removal. Is there a potential for accelerator approval pathway similar to CalcioD approach?

Speaker 3

Yes. 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, I'll put your way of going to at this differently. That's not the original intention of this trial.

Speaker 3

And 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.

Speaker 7

Got it. Thank you.

Operator

Thank you. And our final question for today will be coming from Greg Suvannave of Mizuho Securities. Your line is open. I would now like to go ahead and turn the call back over to Mark Grasso for final remarks.

Speaker 5

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 5 in Boston, Leerink's 2024 Global Biopharma Conference on March 12 in Miami, Barclays Global Healthcare Conference on March 13 in Miami and Stifel's CNS Days March 19th. Thank you again for your time and attention. We'll now conclude today's call.

Operator

This concludes today's conference call. You may all disconnect.

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Earnings Conference Call
Alector Q4 2023
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