Alector Q2 2024 Earnings Call Transcript

Quartr
Provided by Quartr
August 7, 2024

There are 14 speakers on the call.

Operator

Good afternoon, ladies and gentlemen, and welcome to the Elektor Second Quarter and Midyear 2024 Earnings Conference Call. At this time, all participants are in listen only mode. After the speakers' presentation, there will be a question and answer As a reminder, this conference call is being recorded. I would now like to turn the call over to Katie Hogan, Senior Director of Corporate Communications and Investor Relations. Please go ahead.

Speaker 1

Thank you, operator, and hello, everyone. Earlier this afternoon, we released our financial results

Speaker 2

for the

Speaker 1

Q2 2024. The press release is available on our website at www.electra.com, and our 10 Q was filed with the Securities and Exchange Commission this afternoon. Joining me on the call today are Doctor. Arnon Rosenthal, Co Founder and CEO Doctor. Sarah Kankari Mitra, President and Head of Research and Development Doctor.

Speaker 1

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. 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.

Speaker 1

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

Speaker 3

Thank you, Katie. Good afternoon, everyone. We appreciate you joining our conference call today. I'll start by highlighting Alecto's key initiatives during the first half of twenty twenty 4. Then I'd invite Gary to discuss our later stage clinical program.

Speaker 3

Next, Sarah will share the progress we believe we have achieved with Alecto's brain carrier, our proprietary versatile blood band barrier technology platform. Afterward, Mark will provide an update on our financial results and milestone outlook. During the first half of twenty twenty four, we remain committed to advancing our maturing pipeline and are setting the stage for a transformative period ahead. Specifically, we continue to prepare for the data readout from the AL-two Phase 2 trial in VOQ2 expected in Q4. AL-two, our novel Tram2 agonist aims to enhance Tram2 signaling and activate the healthy and beneficial role that microglia play in the setting of neurodegenerative diseases.

Speaker 3

This immuno neurology approach leverages multiple mechanisms of healthy microglia to protect the brain against Alzheimer's disease, potentially offering an efficacy advantage compared to current therapies that target individual misfolded proteins. AL-two is the most advanced tram 2 activating candidate in clinical development worldwide with potential as a monotherapy or as an add on therapy with anti amyloids. Today, we will discuss the patient baseline characteristics reported for IMVOQ2 trial at the Alzheimer's Association International Conference in July. These characteristics confirm a representative study population that enables testing of the effect of ALZ002 in early Alzheimer's disease. We will also delve into the multiple clinical trial imaging and biomarkers readouts for the IMVOQ2 trial.

Speaker 3

Our common close design and statistical BMMRM analysis and our long term extension study, all of which were designed to strengthen the trial analysis. Additionally, Gary will share our thoughts on what the successful data readout look like. In February 2024, the FDA granted breakthrough therapy designation to ratuzinumab for the potential treatment of STD with GRM mutation. You may recall that latuzinumab is a monoclonal antibody that elevates the level of the immune regulatory protein progranulin by blocking sotillin. The breakthrough designation that provided the opportunity for increased interactions with the FDA on this program And now we have additional clarity on how key biomarkers may support our path to a potential regulatory submission.

Speaker 3

We will provide more details on this FDA feedback during today's call. Looking ahead, we believe that we are on track for the pivotal Phase III data readout from INFRONT3 trial in late 2025, early 2026 and we plan to share more specifics soon. Enrollment continues in the progress AD Global Phase 2 clinical trial of AL-one hundred and one for early Alzheimer's disease with dosing initiated early this year. Like latinuzumab, AL-one hundred and one elevates progronorin levels, but offers a distinct pharmacokinetics and pharmacodynamic profile suitable for broader indications. Furthermore, in June, we introduced Electro Brain Carrier ABC, our proprietary blood brain barrier technology platform.

Speaker 3

ABC enhances the delivery of therapeutic agents with greater penetration and efficacy at lower doses with the goal of reducing costs and improving patient outcomes. The introduction of ABC represents a significant advancement in our capabilities to address these challenges of drug delivery in all degenerative diseases. To summarize, we continue advancing genetically validated 1st in class and best in class drug candidates for Alzheimer's disease, frontotemporal dementia and other indications. By targeting genetic pathways implicated in all degenerative diseases and combining innovative science with emerging technology, we continue to strive for a world where degenerative brain disorders are a relic of the past. At this time, I'll turn the call over to Gary.

Speaker 2

Thank you, Arnon. I'm pleased to provide further insights into our later stage clinical portfolio focusing on our advancements with AL-two and our progranulone programs. I'll begin with AL-two. As a reminder, our ongoing INVOQ-two Phase 2 trial, which was fully enrolled in September 2023, is a randomized double blind placebo controlled common closed study evaluating up to 96 weeks of treatment with AL-two in 381 participants with early Alzheimer's disease. This trial includes 3 doses of AL-two, which demonstrated robust target engagement and increased microglial signaling in our Phase 1 study.

Speaker 2

At the Alzheimer's Association International Conference or AAIC last week, Alethor presented participant baseline for INVOKE-two. As Arnon mentioned, the baseline clinical assessments confirm enrollment of the intended population of participants with early Alzheimer's disease. The clinical diagnosis at enrollment was mild cognitive impairment due to Alzheimer's disease for 67% of participants and mild dementia due to Alzheimer's disease for 33% of participants. Notably, participants with baseline amyloid assessments demonstrated a mean centilloid level of 100.1, aligning with expectations for early Alzheimer's disease cohorts. This data marks an important milestone in our global Phase 2 trial, which aims to evaluate the safety and efficacy of AL-two, while testing the hypothesis that this first in class TRM-two agonist may slow the progression of Alzheimer's disease.

Speaker 2

We are on track for the INFO2 data readout in the Q4 of 2024. Today, I'd like to describe the trials outcome measures, our statistical analysis approach, our long term extension study and the expected trial outcomes. The primary clinical outcome is the CDR sum of boxes. We are also collecting secondary clinical and functional outcome assessments, including the ADAS COG-thirteen and ADCS, ADL MCI, from which we will derive treatment effects on the integrated Alzheimer's rating scale or HRIS. This trial will also deliver a robust biomarker package assessing target engagement, treatment effects on microglia and treatment effects on Alzheimer's pathophysiology.

Speaker 2

Target engagement will be assessed by measuring treatment effects on CSF levels of soluble TREM-two. You will recall that in our Phase 1 healthy volunteer study following single doses, we saw dose dependent reductions in CSF soluble TRM2, including changes from baseline exceeding 50% at our highest doses. Treatment effects on microglial signaling will be assessed by measuring levels of CSF1R, SPP1 and IL-1RN, which reflect proliferation, survival and phagocytotic activity of microglia. As previously reported, we saw treatment effects on each of these pathways after single doses in our Phase I study. We are also exploring omics assessments of treatment related changes in microglial subtypes.

Speaker 2

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

Speaker 2

This means we will include data from all participants out to 48 weeks and also include additional data provided by the participants who will have had follow-up for up to 96 weeks. Efficacy will be calculated as the average treatment effect observed across multiple post baseline visits. This approach increases power, potentially enabling us to reach statistical significance at a smaller effect size. If our drug slows disease progression comparable to the treatment effects of the anti amyloid antibodies, we may observe a significant treatment effect. Our ongoing INVOKE-two long term extension study is currently underway for participants who completed the initial treatment period.

Speaker 2

This LTE study remains blinded to treatment assignment, allowing for an ongoing collection of meaningful clinical biomarker and safety data. Thus far, approximately 95% of eligible participants from INVOQ-two have enrolled in the LTE study. In this LTE study, we are also assessing the effects of a modified dose titration on the severity of treatment emergent MRI findings resembling amyloid related imaging abnormalities or ARIA. Participants who roll over from the placebo in the double blind trial to active treatment in the LTE will begin titration at a lower dose than was used in the double blind trial and will also have a slower dose titration schedule. This is intended to explore the effects of starting at a lower dose and using slower titration on the observed treatment related MRI findings that resemble ARIA.

Speaker 2

For context, in the INVOQ-two double blind trial, dosing started at 15 milligrams per kilogram and dose escalation occurred every 4 weeks during the 1st 3 months of the trial. Our hypothesis for the INVOQ-two trial is that treatment with AL-two will increase TRM2 signaling, leading to therapeutic restoration of microglial functions that protect against neurodegenerative disease. This includes the clearance of misfolded proteins such as amyloid, but we also expect AL-two to amplify the broader beneficial effects of healthy microglia on the brain, such as maintenance of synaptic connections, supportive astrocyte and oligodendrocyte function, repair and maintenance of the blood brain barrier and the vasculature and regulation of immune tolerance. Thus, our expectation is that restoration of 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. With its broad and complementary mechanism of action, we expect AL-two to be effective as a standalone therapy and may also demonstrate additive or synergistic effects when used in combination with amyloid targeted therapeutics.

Speaker 2

We also believe that treatment benefits of AL-two may manifest differently from what we have seen in trials of the anti amyloid antibodies. For example, with regard to biomarker responses, lowering cerebral amyloid PET signal to the 24 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. 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 AL-two may have potential to benefit patients ranging from preclinical Alzheimer's disease through advanced dementia.

Speaker 2

Turning now to our pro granulant programs. In a recent Type B interaction with the FDA, we and GSK received feedback on the potential future biologics license application for latasinumab. The FDA has indicated that it would consider the effects of latasinumab on plasma and cerebrospinal fluid progranulin levels as confirmatory evidence supplementing the potential clinical effects of latasinumab pending BLA review. We also aligned with the agency on disease relevant fluid and imaging biomarkers that may be considered as supportive evidence of clinical efficacy, also subject to BLA review. These include biomarkers of astrocyte function, neurodegeneration and brain atrophy.

Speaker 2

Based on the FDA feedback, we remain confident that the totality of evidence, including the primary clinical endpoint and biomarkers could provide a path to potential approval for laduzimab. Following these productive interactions with the FDA, we believe we are on track for the pivotal INFRONT3 Phase 3 data readout in late 2025 or early 2026. In parallel, enrollment continues in the progress AD global Phase 2 clinical trial of AL101 for early Alzheimer's disease. We and GSK are co developing AL-one hundred and one for the potential treatment of more prevalent neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. At AAIC, our partner GSK presented a poster highlighting data supporting the hypothesis that therapeutic increases of progranulin levels may be an effective treatment for Alzheimer's disease.

Speaker 2

These findings demonstrate consistent causal associations between increased progranulin levels and reduced Alzheimer's disease risk across the progranulin gene allelic spectrum, providing compelling genetic evidence for increasing progranulin levels as a potential therapeutic strategy to treat Alzheimer's disease. As we advance these programs, we remain dedicated to harnessing our scientific and clinical expertise to drive forward transformative therapies for neurodegenerative diseases. At this time, I'll turn it over to Sarah for updates on our progress with the Elektor Brain Carrier.

Speaker 4

Thank you, Gary. In June, we held a virtual R and D event highlighting our Elektor Brain Carrier Blood Brain Barrier Technology platform. At Elektor, we've dedicated several years to developing our proprietary versatile Elektor Brain Carrier technology known as ABC. We are leveraging the ABC platform as a vital tool in our preclinical pipeline and novel drug development. ABC enables us to expand our pipeline to include neurodegenerative diseases requiring enzyme or protein replacement.

Speaker 4

It enhances our novel antibody pipeline by improving brain distribution, potentially requiring lower doses and enabling subcutaneous delivery. Additionally, we are also leveraging our ABC technology in the development of 2nd generation drugs towards our pipeline and validated targets. ABC has been validated with multiple therapeutic cargoes, notably we've focused on 2 key transporting targets, transferrin receptor known as TFR and CD98 heavy chain. TFR, a well known ion transport receptor swiftly delivers cargo to the endolysisomal system, while CD98 heavy chain integral to amino acid transport complexes targets cargo primarily across the endothelial cell surface. Both receptors enable effective delivery of functional cargoes, including antibodies and proteins to target itself within the central nervous system.

Speaker 4

Having multiple receptor targets allows us to tailor brain uptake, optimizing efficacy and safety. Our approach with ABC is distinguished by its versatility, tunability and translatability. Our ABC technology is versatile and can accommodate a wide range of cargoes from antibodies to nucleic acids, thus enhancing its application across neurodegenerative disease. Tunability is core to our technology, utilizing a diverse panel of binders with varying affinities to blood brain barrier receptors to precisely match different cargoes, optimizing therapeutic efficacy while ensuring safety. Additionally, translatability from preclinical to clinical species is a key feature and can be important in accelerating our path to clinical trials, ultimately enabling efficient delivery of innovative treatments to patients.

Speaker 4

ABC's capabilities underscore Elektron's commitment to advancing therapies for neurodegenerative diseases by overcoming challenges in drug delivery to the brain, positioning us at the forefront of neurodegenerative disease drug development. Looking ahead, we will continue to provide updates on our ABC programs as they progress, reinforcing our dedication to pioneering new frontiers in brain health. Now, I'll turn the call over to Mark for an update on our financial results and milestone outlook.

Speaker 5

Thank you, Sarah. We summarized our Q2 2024 financial results in the press release that we made available after the market closed today. First, I'll highlight that we remain well funded to execute our strategic objectives. We ended the Q2 of 2024 with a strong cash position of $503,300,000 Our cash runway extends through 2026, demonstrating robust financial preparedness for future growth and financial strength through the completion of key milestones, including the AL-two INVOK2 Phase 2 data readout and the pivotal INFRONT 3 Phase 3 data readout for latasitimab, with the runway coverage extending approximately a year beyond the INFRONT 3 readout. Turning now to 2024 financial guidance.

Speaker 5

We continue to anticipate collaboration revenue to be between $60,000,000 $70,000,000 We have tightened our total research and development guidance to be between $210,000,000 $220,000,000 We have reiterated our total general and administrative guidance to be between $60,000,000 $70,000,000 We are well capitalized with a robust cash position and remain focused on advancing our later stage and ABC portfolio. We look forward to providing additional updates as we progress our work. That concludes our prepared comments for today's call. Operator, you may now open the line for questions.

Operator

Thank you. At this time, we will conduct a question and answer session. And our first question comes from Paul Matteis with Stifel.

Speaker 6

Hi, there. This is Julian on for Paul. Thanks so much for taking our question. So a couple from me. On TREND-two, do you mind just reminding everybody, what proportion of data from participants out to 48 weeks 96 weeks and somewhere in between you expect in this upcoming readout?

Speaker 6

And also, do you plan on rolling over APOE4 homozygotes that were in the placebo group to your long term extension study? And then also on latuzinumab, can you just clarify what exactly does it mean that the FDA would consider plasma and CSF PGRN as confirmatory? I guess to me it seems a little unusual as biomarkers for a biomarker to be confirmatory evidence of clinical benefit. Usually it's predicting clinical benefit in the absence of clinical data. So any additional color would be really helpful there.

Speaker 6

Thank you.

Speaker 2

Yes. This is Gary. I can take that. So I think your first question was around TREM-two. What is the how many patients do we have at the different time point?

Speaker 2

So all of the patients, all the completers, which we expect to be around 250, will complete 48 weeks of treatment. And then we'll have about half of those, we'll have 72 weeks of treatment and about a third, we'll have 96 weeks treatment. I want to just remind you that our LTE remains blinded to original treatment assignment, which means that we'll still be having be able to collect meaningful data on biomarkers and safety, but also on clinical outcomes given the blindness and the fact that and that will be up so 6 months later we'll have a minimum of 72 weeks of data on all patients and then 6 months later 2 years of data. Your second question was about the LTE, I think about rollover of APOE homozygous. No, we are rolling over the placebo group, which is which like the rest of the study at the current study population does not include APOE4 homozygous anymore.

Speaker 2

They were we stopped enrollment early in this study and discontinued them because we saw more severe MRI changes resembling ARIA in the APO A4 homozygous. So they are not rolling over in the LTE. And I think your last question was about latazinumab. What does it mean to be confirmatory evidence of clinical benefit? It means that if we have a clinically a positive result on the primary clinical outcome measure, which is the CDR that the CDR FDD, FDLD, NAC, it's basically a CDR with 2 additional modules for behavior and language difficulties, which FDD patients have.

Speaker 2

And what it means is that, we discussed some specifics about some of the biomarkers, imaging and fluid biomarkers that we would use, including GFAP and NfL and region of interest volumetric, I should just say, volumetric MRI that they would be if we were to see effects on those biomarkers that would be added confirmatory evidence of the effect on the clinical outcome measure. It does not mean in this context that it would be that the biomarkers would be surrogates for the clinical outcome measure. However, that said, I mean, we are also fully cognizant that there are many similarities here in FTD to drugs like to Versant that was approved based on an accelerated approval based on very some of the same biomarkers, NfL predominantly. And likewise, in this study, we see these biomarkers are prognostic and FDA. We had a discussion with this about those similarities.

Speaker 2

And so if our for some reason and we don't expect this, but if especially based on our Phase II data, which was very promising, we expect that if we did if we were disappointed by the clinical outcome, but we saw directional effects, I mean, we think that a backup strategy could be an accelerated approval approach. We have not discussed that with FDA yet, but I think that they're we're encouraged by their endorsements of the biomarkers that we suggested.

Speaker 6

Got it. Makes sense. Thanks. Appreciate it.

Operator

One moment for our next question. And our next question comes from Alex Stranahan with Bank of America.

Speaker 6

Hi, this is Susan on for Alex. He had a question about INVOK2. How should we be thinking about patients enrolling in a long term extension study for ENVOQ-two in terms of tolerability and efficacy?

Speaker 2

Yes. Thank you, Susan. So how do we think about patients enrolling in LTT around efficacy and safety? Well, first, I have to tell you that we're very pleased by the fact that up to this point, 95% of patients that have been eligible to roll over, and that's most of the patients by far, have decided to do so and are now in the LTE. Some have actually completed the LTE.

Speaker 2

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

Speaker 7

Thank you, Sue. Operator, I think we're ready for the next question.

Operator

One moment for our next question. Our next question comes from Jeffrey Hung with Morgan Stanley.

Speaker 8

Hi, this is Michael Reade on for Jeff Hung. Thank you for taking our questions. Going back to the baseline invoked data, so 2 thirds had mild cognitive impairment and the third had mild dementia. But you also saw mean amyloid like pet centilloids of around 100 at baseline. Are you able to say whether that differed between the two populations in terms of cognitive impairment versus dementia?

Speaker 8

And also it's not a full capture of the total trial population. Is that something that will get resolved? Thanks. And I have a follow-up.

Speaker 2

Yes. So I can't tell you. I don't we don't have the data broken down by the MCI and mild AD regarding the senileg levels. I don't have that. We just looked at the aggregate senileg levels.

Speaker 2

And we I can see if I missed your other question. I didn't catch the question about full capture. I didn't quite follow what you're asking.

Speaker 8

Sorry about that. I just not like I thought it was like in the low to like mid-200s and the child had enrolled more patients. Like is mean amyloid PET at baseline something that would be captured for the whole population or just the, like the 244?

Speaker 2

Yes. So at the this was baseline characteristics. So this was what we reported out on was the number of patients that was where the patients that had used amyloid PET for inclusion and therefore had a baseline amyloid PET scan. So that would include everyone up to that point that for which we had data, which would be everyone because they were fully enrolled. Yes, so that's the hope does that answers your question?

Speaker 8

Yes, no, that's very helpful. And then just as a quick follow on, like what sort of follow-up, what would you think is the expectations for celluloid reduction in INVOQ?

Speaker 2

That's a good question. So since we see this MRI finding that resembles ARIAP in every manner, We wouldn't be surprised to prorhring amyloid. We also wouldn't be surprised given that the fact that this is a we believe that AL-two will restore microglial function and we know that microglia are involved in compacting and also clearing amyloid and other misfolded proteins in during under regular conditions and also are involved in removal of amyloid after they get tagged by anti amyloid antibodies. So it doesn't surprise us that we would see that. In terms of the expectation, we don't know yet and we haven't yet looked.

Speaker 2

But I would tell you that we don't see I think this is really important point. This is really a this is a truly different mechanism than anti amyloid antibodies. And it has as we described in our presentation, we are by restoring microglial function, we're restoring many different downstream mechanisms by which microglia preserve brain health. So we don't this is really not intended to be just an amyloid lowering agent. Therefore, if we do or do not reach the amyloid, the 24 centenoid level that seems to be a necessary condition for clinical efficacy for the anti amyloid antibodies, that's not going to bother us.

Speaker 2

And we're not going to make a decision based on that because this really goes beyond amyloid clearance, this mechanism.

Speaker 8

Thank you so much. I really appreciate that.

Operator

One moment for our next question. And our next question comes from Pete Stavropoulos with Cantor Fitzgerald.

Speaker 1

Hi, this is Samantha on the line for Pete. Thanks for taking our questions. Firstly, for TRM-two, can you give us an idea of what to expect for the first data release next quarter? What's the bar for moving this program forward into a later stage study? Will it be biomarker driven?

Speaker 1

Or do you need to see a clear signal of clinical efficacy? And regarding safety monitoring, is it safe to assume that ARIA like observations have been minimized due to the protocol changes? Has there been any new KOL feedback on what might be driving these observations? And finally, regarding the ABC technology, could you describe the tissues or cell types where CD98 is expressed and outline any theoretical risks associated with targeting CD98? Thanks so much.

Speaker 2

Okay. Thanks. Good questions. Thanks, Samantha. So what you expect data we're going to report, we're going to we'll have a press release and that press release will include not only the typical top line, primary clinical outcomes and safety, but we're also going to include data on the relevant biomarkers.

Speaker 2

As I said, this is we're making a decision based on a combination of clinical, functional and biomarker readouts. We have lots of biomarkers. So all of those that are relevant to making a decision, particularly the Alzheimer's physiology biomarkers will be included. We'll be reporting out on we intend to report out on all of those at the same with the press release, not just top line. And what is the bar to advance?

Speaker 2

I just said it, right. It's some combination there of and seeing consistency across those clinical and biomarker outcomes that showing that we are slowing disease progression because that's in the end of the day, that's what we're up to do. So it's not going to be about hitting a P value or on just clinical outcome measure that that's if we do or don't, if we see directional effects there consistent with biomarker directional effects showing slowing of disease progression, For us, that's a win and that's a we'll be very excited to see that and advance the compound. You also asked about ARIA. Is it do we think it's minimized?

Speaker 2

Well, what we do know is that when we after we dropped the APOE-four is we then added MRI surveillance. And MRI surveillance, actually, we were doing it every 4 weeks before each dose titration for the 1st 3 months and then less often after that. We know that likely increases the amount of area you're going to find because you're looking every 4 weeks for radiographic area, which is 90% of the area. Lilly, by the way, reported that in their Venetimab Phase 3 program that they added area surveillance, increased the area surveillance, they saw more area. Also they saw in addition to seeing it more higher incidents, they also found that the severity was reduced.

Speaker 2

And we've also observed that, as I said, the incidence and severity of ARIA actually come down for us in our study under the current population. Is it minimized, meaning is that as low as it can go? I don't know. We don't know that for sure, but I can tell you that in our long term extension, one of the things that we're exploring is whether starting at a lower dose and titrating more slowly akin to what they've been doing in the amyloid anti amyloid antibody trials could reduce the ARRU signal. So that we hope to learn that as well in our long term extension study.

Speaker 2

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

Speaker 2

And I think there's a CD98 question for Sarah.

Speaker 3

Yes. Yes. According to the human protein address, sort of CD98 is expressed in endocrine tissues, in the pancreas, in the kidney, in genitalia and a little bit in the skin. So yes, we will be looking if there's any adverse effects in these tissues. In the brain, CD98 is expressed higher in support cells in microglia and astrocytes and in lower levels in neurons outside of the endothelial cells, which enables using it as a blood and barrier transport.

Speaker 2

This is so helpful.

Speaker 4

Thank you so much.

Operator

One moment for our next question. Your next question comes from Yaron Verber with TD Cowen.

Speaker 6

Hi, this is Brendan on for Yaron. Thanks for taking the question guys. Actually just a quick one on the potential AbbVie opt in payment. Can you maybe just remind us

Speaker 9

when what

Speaker 6

the timing is to potentially book that? If the data comes out Q4 and looks good, do you expect them would you expect to book that after the Phase 2 data maybe in Q1? Are there other gating factors there? And just kind of let us know how you would report that. And then honestly just looking at the deeper pipeline, just wondering which of the target programs you might expect to enter the clinic first?

Speaker 6

When do you think that might happen? Thanks.

Speaker 7

Yes. Thanks for the questions, Brennan. So as it relates to the option payment with AbbVie, as you recall, at their option $250,000,000 at the end of the Phase 2. So we're aligned with them around the proof of concept study package and we plan to be sharing that package with them at the end of this year Q4 of this year. And if they have 90 days, both they're accepting for that package to decide if they're opting in.

Speaker 7

So that would put the payment towards the end of Q1, early Q2 is our expectation currently. And then your second question around which of the programs in our earlier portfolio will be advancing and which is the most advanced. We have a number of disclosed programs and a number of undisclosed programs and we look forward to providing you updates around that portfolio as next year progresses in the coming years. We haven't specifically made a statement at this time as to which one is advancing first. Hopefully that helps, Brennan.

Speaker 6

Yes. That's great. Thanks, guys.

Operator

One moment for our next question. And our next question comes from Carter Gould with Barclays.

Speaker 9

Good afternoon. Thanks for taking the question. I guess first off, I want to be clear on exactly what's sort of being messaged coming out of that Type B meeting. It's appreciating your affirmation of confidence in the primary endpoint, but it sounds like this is a contingency strategy in the context of a potentially equivocal data on the primary. Is that a fair characterization?

Speaker 9

And does this in any way represent an evolution of your regulatory strategy on that program? And then, I guess just to follow-up on coming out of INVOQ-two, it sounds like there'll be a separation of data and path forward. So I guess, again, is that sort of a fair characterization that we shouldn't expect any sort of commitment on moving the product forward necessarily when we get the data. And I guess alongside that as we think about AbbVie and their decision process, they did recently deprioritize or discontinue their A beta program. How do you view that?

Speaker 9

And if there's any read through to 2? Thank you.

Speaker 7

Thanks for the questions, Carter. Maybe Gary, you can take the first question and I'll take the latter 2.

Speaker 2

Yes, sure. So Carter, thanks for your question. No, this really is not a contingency strategy. We are committed and we're optimistic that we can get a full approval based on the primary outcomes, secondary outcomes and the biomarkers. Our questions were really, can we are these the biomarkers?

Speaker 2

There's a lot of biomarkers one could look at. We felt that the ones that we proposed were biomarkers that if we were to see effects, these are biomarkers that are prognostic to begin with. So if you see changes in NfL or GFAP even before there are symptoms, You see changes in volumetric MRI even before symptoms. So it's a prognostic biomarker. We don't know yet whether it is a surrogate marker, but we would imagine that because you see these changes even in advance of clinical symptoms that changes in the trajectories of these biomarkers should support the clinical outcome.

Speaker 2

This is a single study. It's a rare disease. So it's a relatively small study. It's 100 patients. And so we're always thinking and looking about how to devise our statistical analysis plan in a way that can best show that the drug is providing benefit.

Speaker 2

And we thought these were important questions to ask. If they didn't think these biomarkers were relevant or good enough or whatever, then we would have to maybe think differently about our SAP, but we are very encouraged by this information. We really are committed to for a full approval based on the totality of the data.

Speaker 7

Yes. And I think your second question Carter related so we were answering the question prior analyst was asking about the I think the earlier pipeline in which program would advance next not referring to TRM-two. That program obviously subject to AbbVie's opt in decision that would be a component, but we're looking forward to advancing that. We expect the next stage would be a Phase 3. If they opt in, they would be taking on that Phase 3 and we share fifty-fifty in the cost and also the profits as that program advances.

Speaker 7

And remind me your third question,

Speaker 9

Carter? Again, any read through from AbbVie's decision to deprioritize or discontinue their abeta program sort of on some level you could say that's narrowing their Alzheimer's portfolio and you see any read through then to around their interest in 2? Thank you.

Speaker 7

Yes. It's really hard for us to speculate there. Maybe they didn't see the differentiation they were looking for with that A beta program relative to what else is out there. Again, we remind the broader mechanism and the complementary role that activation of microglia can play. So we don't necessarily see a read through there, but that's our speculation.

Speaker 7

What we can say is we're very aligned with that be including around, as I mentioned, and as Gary has highlighted, the Phase 2 data readout and proof of concept study package that's associated with that.

Speaker 6

Thank you.

Operator

One moment for our next question. And our next question comes from Tom Schroeder with BTIG.

Speaker 6

Good afternoon. Thanks for taking the question. There on progress AD, the trial with 101. Have you seen or are you going to update us if you're going to see if you've seen the MRI signal characteristic of ARIA? It's obviously interesting here, but at some level, it doesn't de risk the entire pro granulant program if you did see some ARIA?

Speaker 2

Yes, that's a good question, Tom, as always. We don't have any reason well, because this mechanism of action involves, we think involves microglia, we have built into the study MRI surveillance to look and see if we have ARIA. I can tell you that we haven't seen any such signals thus far, study, it's early days with that study. Would it derisk the program, you mean in the sense that it would somehow So you have

Speaker 6

to say extracellular sort of does what it supposed to.

Speaker 2

Yes, I suppose so. I mean, I think, yes, I mean, I think in the same way that we think about it in AL002, it would be in some ways encouraging about biological activity. But so far, we're looking mostly to make sure we don't miss a safety signal that we need to keep an eye on. But we haven't seen anything else yet.

Speaker 6

And real quick, is increasing pro granulant to high levels based on the biology that you guys are so into, is that as broad an effect as increasing TRM2? It almost seems like a step backwards that you're fixing the lysosome and hoping everything else follows rather TRM-two forces everything. Is that a fair characterization?

Speaker 2

Arnon, do you want to I'm happy to answer that or if you, Chris, you want to speak to it.

Speaker 3

Yes, it is a different mechanism, but for granularlyne also has a liposomal chaperone, as you said, it enhances liposomal activity, which is a critical component in fighting misfolded protein, but it's also a survival factor for multiple types of neurons. It sort of enhances sort of neuronal activity. So we think that, yes, these are different mechanisms and we think that because now the generation is such sort of such a large unmet need, it's worth testing multiple mechanisms. We don't think that progalony is less broad or is sort of it's similar to anti A beta antibody, for example. We think that progalony is sufficiently broad to address multiple disease pathologies.

Speaker 5

Okay, great. Thanks for the details.

Operator

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

Speaker 10

Hi. You've got Sarah on for Myles. Congrats on the progress and thanks for taking our questions. So can you just remind us whether all doses tested in IMOKE-two would potentially be therapeutic? And as it relates to your powering assumptions, are you expecting to pool those treated patients or consider each dose arm individually?

Speaker 10

And second, now that we've seen the baseline characteristics, in your view, how do these patients compare to those enrolled in other AD therapeutic trials we've seen regarding severity, stage of disease and biomarkers? And do you think the entire range of dosing, including 48 weeks, will be long enough to see a measurable function decline in the placebo group to potentially separate from those treated patients?

Speaker 2

Well, there are great questions. Thank you. So, do we think all doses are therapeutic? Well, yes, because in our Phase 1 study, we saw target engagement, so reductions in soluble TREM2. They were highest in the top two doses where we saw greater than 50%, but they were still robust in the low dose that we're testing and even lower than that.

Speaker 2

So based on that, I think that that is it would be therapeutic. We also saw increased microglial signaling across multiple pathways IL-1RN, I think we mentioned this in the call and CSF-1R and SVP-1 at all those doses. So yes, we do think that those are potentially therapeutic. In terms of the analysis, so we will look at each dose versus placebo, but we will also be pulling data. And in fact, the top two doses are overlapping considerably in their PK.

Speaker 2

And so we will that's definitely part of our pre specified it's a pre specified analysis that we'll be looking at definitely. How do the patients compare to the other anti amyloid antibodies? Really right down the middle, I would say. I mean, the senoloid level is a bit higher than in A size lekembi, but it's a little bit lower than what they saw in denanumab, the same thing for the distribution of clinical diagnosis. And based on the data we had, it really looked right down the middle.

Speaker 2

So we were very pleased with that. And I think the last question was, does the entire range of dosing, right, right. So I think you're asking about with the duration of 48 weeks be enough. This is one of the reasons for the common close design here was that this is a novel mechanism and we can't necessarily expect that the temporal dynamics of treatment effects of restoring microglial function will all happen at the same time, right? I mean, if there are effects on clearing amyloid and synapses, we might expect those earlier.

Speaker 2

If there's effects by restoring the maintenance functions of supporting all good endocytes and astrocytes and the blood brain barrier and the vasculature, immune tolerance, those could take potentially could take longer. So we do think that 48 weeks, we should we hope to see something at 48 weeks. We will have data out to 96 and that's one of the reasons we and AbbVie really wanted to invest in the long term extension to be blinded to treatment assignments so that we could get meaningful data even after the double blind, we left the study in the double blind. So I think some of those manifestations could be early, but we think that the full effect of this mechanism may it's possible that we that will take longer to see that. Hopefully, we'll get to see that in those that have data out to 72 weeks and even those out to 96.

Speaker 2

But if it's emerging, we'll we have the study design to be able to capture that.

Speaker 10

Makes sense. Thank you.

Speaker 2

Thanks.

Operator

One moment for our next question. And our next question comes from Ananda Ghosh with H. C. Wainwright and Company.

Speaker 11

Yes. Hi. Thanks for taking the question. I have a couple of questions. The first one is, of course, on the Type B meeting.

Speaker 11

So just curious, given FDA's encouraging stand in the Hunter syndrome, where they might consider heparin sulfate as a surrogate biomarker? Or if you look at ALS, the 2 for some example, which you mentioned, what has been your like takeaway like how open FDA might be to consider some of the biomarkers like prokradulin itself as the surrogate biomarker for the PGRN program going forward?

Speaker 2

Yes. Thank you. I agree with you that there's been a lot of I think there's been some regulatory flexibility and certainly when it comes to rare diseases that they seem to have been more so more flexibility in how they and especially in considering biomarkers to be supportive or even enough for approval. And you gave some good examples. We're encouraged by that.

Speaker 2

That doesn't but we are still we still feel that we have a very good shot at a full approval with a more traditional approach. That said, if we're disappointed somehow with what the clinical outcome measure here, which we think we are going to have a really good backup to if we see biomarker changes as we expect to see. So I think we are encouraged by that flexibility, but a full approval for us is I think it's not debatable. It's like it would be better for for patients, better for us if we could get a full approval.

Speaker 11

Got it. A follow-up question on the program is at the European ALS Conference, a lot of KOLs actually pointed out that and now it's kind of well established. In case of tofersen, you see the NFL drop much before than you see the clinical benefit coming from tofersen in SOD1 mutant patients. So for your pro granuline program, have you thought about thought like have you is there a way to kind of to also track that where you see the clinical benefits kind of lags behind the drop in some of the key biomarkers or the way the biomarkers are progressing?

Speaker 2

Yes. I agree with you. And we the same is true in FTD. You see changes in NFL before you see clinical signs and symptoms. That's why in our study, we originally started out including patients who were asymptomatic, but we knew that were at risk because they had it for granular loss of function mutation and they also had elevated NfL levels.

Speaker 2

We originally planned to include that in our primary analysis, but because they were they're hard to find and we had very fewer of them and because they had a lot of variability to the progression rates, Last year, we went to FDA and EMA and we proposed to focus on the symptomatic patients for the primary analysis, but we will still analyze that data in the pre symptomatic patients as a sensitivity analysis. So and we're very excited about that. We think if it's going to work in symptomatic patients, it may work even better in the early patients and in the pre symptomatic patients. So you know, and yes, we may we'll see when we look at our data whether we see changes in NFL that precede the temporal dynamics of effects on those biomarkers versus the clinical outcomes.

Speaker 11

Got it. And I just have 2 questions on the TREN2. The first one is both Biogen and obviously Lilly has done this, the low tau, how tau like and high tau like analysis for their EDI trials. So what have you like do you have plans to kind of do a subgroup analysis later on where you are looking at low tau or high tau in and to kind of figure out what how the AL-two impacts in this kind of population? And the second is how fast the ramp up might be for your titration schedule for AL002?

Speaker 2

Yes. So, okay. So, about the tau, a question about will these tau tersiles. Yes, that's definitely part of our pre specified analysis. We're going to we will have P217 in every patient.

Speaker 2

So we can do it by P217 levels. We will also have Tau PET in a smaller subset, but we're doing it mostly based on plasma P tau markers. We are going to look at those terciles. That, of course, will tell us will give us some indication of whether we are seeing differential effects across the disease spectrum in low tau or mid tau patient or high tau patients. That said, we really don't expect to see these differences as much with this mechanism than you would with an anti amyloid antibody where there's more of a defined window of the pathophysiology that where it may work the best.

Speaker 2

The second question is about the ramp up. So in our study, when we went to a titration, it was every 4 weeks was the increase in dose. And that's why we as I mentioned earlier that we were putting in MRI surveillance. We're slowing that titration down and starting at a lower dose in the patients that roll over in the LTE, because we want to learn whether that could be mitigating for the area.

Speaker 11

Okay. Thank you very much.

Speaker 7

Thanks, Ananda. Good questions. Operator, I think we have time for 2 more here.

Operator

One moment for our next question. Our next question is from Gregg Savanovich with Mizuho Securities.

Speaker 12

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

Speaker 12

Thanks.

Speaker 2

Yes. So this proportional method that we're using or proportional MMRM, as I mentioned, it allows us to look at it's really particularly helpful in the common close design where we have patients with different durations of treatment And we can use all of that data as I outlined. This is a novel method, but it has been used before in Alzheimer's trials in one of the Diane studies, it was used. And also, I believe that really used it in as a sensitivity analysis in their Phase II and possibly want Eisai, I don't remember which study that was. So it is novel, but others have explored it.

Speaker 2

Yes, I think it's for us, we thought given the common close design and given that we were trying to make this really a biomarker rich study, we would have a lot of different types of readouts. We thought that this would be the best. Willie and I should say AbbVie agreed around this design some years ago before the study started. So yes, I mean, we'll also do sensitivity analysis with other more traditional approaches, but this is our primary outcome.

Speaker 7

Thanks for the question, Greg. Operator, I think we have time for one more.

Operator

Our next question then comes from Corrine Johnson with Goldman Sachs.

Speaker 13

Yes, thanks guys. Good afternoon. Maybe could you just talk a little bit I think I understand, but if you could just square the comments you've made around containing the mechanism as related to amyloid clearance, but that you don't have to get the same degree of central reduction to kind of see clinical effect? And then maybe you could expand a little bit more on the cash runway guidance, particularly with respect to which activities around the ABC platform are going to be embedded within that timeframe?

Speaker 2

Yes. So I'll take the first one, Karim. Thanks, sir. Good question. Yes.

Speaker 2

So what I was referring to is that so our hypothesis is that increasing Trem2 signaling triggers a number of other signaling pathways that allow for proliferation of microglia, increased function and survival. And we think that this is going to shift the population of microglia. We know that with aging and with neurodegenerative disease, you have senescence of microglia. So by shifting the microglia to more healthy and active and functional microglia, we'll have that all those beneficial effects that come, I won't repeat that, that come from microglia, including amyloid clearance and clearance of misfolded proteins. And by the way, it's interesting that we're focused not on amyloid because of the potential area like signal.

Speaker 2

But there's lots of comorbidities that are usually seen with Alzheimer's disease. So microglia are not selective for amyloid. They would clear TDP-forty three and they would clear other alpha synuclein and the like. So we think this is why we're so excited about this mechanism. When I say it doesn't need to reach the 24 centenoid level, I think for an anti amyloid antibody, that's what it does, it lowers amyloid.

Speaker 2

It looks like there's now plenty lots of data showing that curve. You've seen the graphs, I'm sure, where it show that you need to get to a certain level before you start seeing clinical benefit. I mean, the gantenerumab study is an example of one that didn't quite get there. And in aducanumab, one of the studies didn't get there, didn't have clinical the clinical data were less robust. So it looks like you have to get down to this 24 centenoid level, if that's your mechanism you're using.

Speaker 2

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

Speaker 2

I can add

Speaker 3

to this a little bit. There are data even in human that microglia in a tram to dependent manner can contain A beta without removing it. They form a barrier between the A beta plaques and the surrounding neurons and they basically make the A beta plaques in nerves. The A beta plaques can no longer injure the neurons. So you can get therapeutic benefit even on A beta without removal of A beta if you recruit the microglia.

Speaker 10

I see.

Speaker 3

And in addition, yes, as Gary said, the microglia responsible for replacement of damaged synaptic connections in Alzheimer's disease up to 50% of the synapses can be damaged. They are responsible for the replacement of damaged myelin, there is significant myelin damage in Alzheimer's disease. They are responsible for direct novel transmission without functional microglia, novel transmission is abnormal. So there are a lot of other activities that should translate to clinical benefit independent of A beta pathology.

Speaker 7

And just on the cash runway guidance, Corinne. So we reiterated that our runway is through 2026 and that's a full 2 years beyond the expected TRIM-two data readout end of this year and a full year beyond expected FPD Phase 3 readout end of next year and doesn't assume any opt in from AbbVie or other milestones or business development. So we think that's a pretty healthy runway and a strong position as it relates to the Electra Brain Carrier portfolio. We're going to provide more updates as that program progresses as those programs progress. We haven't said specifically what that would advance those programs through, but you could expect that that would be through INDs on programs.

Speaker 6

Correct. Thank you.

Speaker 7

Yes.

Operator

And this concludes the question and answer session. I would now like to turn it back to Mark for closing

Speaker 7

remarks. Thanks everyone for the thoughtful questions. Before we end the call, I'd just like to share we will Morgan Stanley Annual Global Healthcare Conference September 5 in New York H. C. Wainwright's Global Investment Conference on September 9 in New York and Cantor's Global Healthcare Conference on September 17 in New York.

Speaker 7

Thank you again for your time and attention today.

Operator

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

Powered by Quartr
Earnings Conference Call
Alector Q2 2024
00:00 / 00:00