Alector, Inc. (ALEC) Earnings Call Transcript & Summary

Okay. Welcome to the afternoon sessions of the Second Annual Virtual Napa conference. Next here will be the real thing. Fingers crossed. My name is Geoff Meacham, I'm the senior biopharma analyst here, and I have Alex Hammond from my team with me as well. And we're thrilled to have Alector with us for this last session and speaking on behalf of Alector is President and COO, Shehnaaz Suliman. How are you doing, Shehnaaz? It's good to see you.

Doing great. Thanks for having us.

Yes. So we'll start it off with maybe just sort of a recap of the events of early last week with Biogen's aducanumab obviously, doesn't directly affect you, but I wanted to kind of get your thoughts of the FDA decision and maybe what that means for Alzheimer's or neurodegeneration drug development?

Certainly. So I'd have to say that at a macro level we were encouraged that the FDA has adopted a broader stance on what could be required for approval in neurodegeneration and in AD in particular. And I mean, really, this is what the field has been campaigning for, for quite some time, which is a more holistic approach and looking at biomarkers or target biomarkers in addition to cognitive endpoints and volumetric MRI. So I think the willingness to engage in a dialogue, which is broader and the ability to potentially consider an approval, given the totality of the data set that can be generated were certainly encouraging. We think patients and physicians alike will be very encouraged by the news. What it means for us, though, I think is that we've always considered ourselves a different therapeutic approach, our immuno-neurology approach is really focused on activating the brain's innate immune system and microglia specifically to address neurodegeneration. And so our approach is entirely complementary to any potential anti-A-beta or anti-tau modality, which might be out there. And so we just -- we feel that -- again, it's opened the door for a broader dialogue with FDA, and we've been engaging with FDA quite intently in that regard as well. But I also feel like the efficacy threshold for aducanumab is modest enough that the opportunity for synergistic therapeutic effect is there. And so from our point of view, it's all good because we see that what could be considered clinically for patients, there's still an opportunity to improve, certainly and as it results to either FTD or AD, I would say, on balance is very encouraging.

Great. That's helpful. Yes, let's ask -- let's focus on the AD kind of read-through. I mean I agree that it definitely we'll advance the field. There's a lot -- I wouldn't -- the bar, I think, is just different now. But when you look at therapies that are not PET imaging and beta amyloid biomarker specific, how do you -- does that add some complexity? Because obviously down the road you want everything to go vis-a-vis the cognition route, right? We want everything to be validated. That's the true measure. But we do have a little bit of a shift now in just the biomarker component of it though. How does that -- does that affect you guys? And how you think about combinations maybe down the road?

Yes. I mean I think it's all positive momentum, and this is where at our Investor Day that we held recently, we tried to guide to specifically this notion that what you really want to do is to figure out the temporal relationship of different biomarkers in relation to your specific mechanistic pathway. So in our case, the upregulation of progranulin and the associated disease cascade that service markers of the underlying pathophysiology and FTD is what we're trying to get to. That composite view of which biomarkers change in which sequence in order to help characterize the impact the treatment can have on the natural history of the disease. So I think that work is ongoing. We're going to continue to collect all those biomarker data in our Phase II, coming up which we'll show some of that data at AIC, but also in the Phase III, more importantly, to enable us to leverage the momentum from FDA's now broadened approach to discuss more than just a cognitive endpoint as a potential enabler for approval. I don't disagree that at the end of the day, what clinically meaningful is changing a cognitive endpoint. But as we're all aware, there are -- there are limitations to CDR Sum of Boxes or our bands or any of these cognitive assessments, which have tended to make getting them -- making them specifically viable, quite difficult in the past. So the readthrough effect is actually very positive, and we've been having some of the conversations with FDA. So I think they've been quite consistent in their philosophy, and we look forward to continuing those conversations.

That's fantastic. And not just on biomarkers, but on interim analysis, do you think that, that -- does this perhaps change the way that you get to a derisking event in a more rapid way. I know a lot of companies are now thinking, well, maybe we'll add more patients to a trial and then call it interim efficacy analysis at 1-year as opposed to a typical Alzheimer's meeting or Alzheimer's endpoint, which could be 18 months or even 24 months?

Well, I mean, I think the verdict was out on the question of whether the biomarker is robust. And in this case, the FDA rule that they thought that it was. There's obviously still some debate in the field about whether or not you can correlate an anti-amyloid therapy with clear cognitive benefit. And I'd say the Holy Grail is being able to correlate biomarkers with clinical outcomes with a greater degree of statistical rigor that enables that thesis to actually pan out. From our perspective, we have open-label data, which is interesting and allows us to take look at the data in FTD. I think in the Phase III, will really be the definitive opportunity to think about associations and correlation. As it relates to AD, I think you still have to power the trial for a clinical endpoint at the end of the day, whether your Phase II/III is part of an approval package or not. And our TREM2, we're lucky in that we have soluble TREM2 as a clearly validated biomarker of target engagement. And so In our case, we're looking at both soluble TREM2 as well as other markers of microbial activation in addition to a cognitive endpoint in a well-powered Phase II that provides interesting opportunities, again, at the end of Phase II meeting with FDA.

Got you. Okay. That's helpful. Well let's focus on the FTD program. And we learned a lot last week at recession. So I wanted to maybe just ask you, when you think about what is clinically meaningful, We kind of know that from experience in Alzheimer's, I'm in FTD. Maybe just help us with what would a positive result look like considering the 6- and 12-month endpoints, maybe too early, but you may have biomarkers that can give you a little bit more validation in terms of the validation of the clinical effect?

Indeed. So when we have a discussion with key opinion leaders and our principal investigators, there's no question that a 30% to 40% reduction in the CDR-NACC-FTLD is what's considered clinically meaningful. It really is the threshold and in AD, it's quite similar if you ask a spectrum of [indiscernible] leaders about what's the threshold for efficacy. They usually net out at around 30% to 40%. I think in FTD you could actually make a case that 25%, Jon Rohrer and others have been quoted as saying, it's even lower than that because you really have no approved therapy at all, not even a symptomatic approved therapy. So -- but I think that 30% to 40% range on the CDR-NACC-FTLD, feels like the right range. And our Phase III have been powered to show that. I think as it relates to the others, there's obviously a great degree of healthy debate around neurofilament as one of the key biomarkers that indicate neuronal degeneration or improvement. And I think there too, we've moved away from having to rely on neurofilament solely because of the spectrum of disease idea. And the fact that inflammation, complement activation, lysosomal function, which is a key hallmark of FTD are actually far more important and for more proximal indicators that progranulin which has been up-regulated is actually trafficked through the lysosomes Tom and functioning the way you would expect wild-type progranulin to function. And so that's why, I think, seeing an appropriate decline -- a change from baseline, who ever the disease causes, baseline inflammations to go up or down and seeing the effect of a treatment -- AL001 treatment effect across several biomarkers, plus or minus neurofilament would be considered directionally, really encouraging. And then, of course, if we see a change in the CDR-NACC-FTLD, it always feels that critical data will trump everything. And the MRI, there's some methodological constraints depending on how you look at it, whether it's T1 or T2 weighted. And again, small numbers of patients. We said 9 patients. So I think we just -- I think that everyone is appropriately titrated to what this data could show. But I think trends into 2 more of the 3 or 4 modalities that we're looking at, will be very encouraging. And the other thing, of course, that we've decided to do is look at the matched control as the opportunity to determine -- to contextualize our data. And I think that will be important, particularly for the cognitive piece, which is looking at a similar stage population from GENFI, that as the frame baseline level of disease that has been matched from your opponent level at entry, age and gender, and determining how data set compares with that data set at 12 months will be interesting.

Thank you. That was a lot of information, very important. So moving on to the Phase II data release. What is the baseline disease severity and degree of variability you're expecting for patients imaging and clinical progression? And are these patients going to recapitulate the patient population you're targeting for your ongoing Phase III trial?

Yes, it's a good question. So I think the spectrum is 0.5 to 2 in CDR-NACC-FTLD, which is on the milder end of the spectrum, mild-to-moderate. I think for the Phase III, we're looking at the same patient population. And we -- that's part of our inclusion criteria for the symptomatic cohort for the at-risk patient cohort. There, we have patients stratified by neurofilament cut point. [indiscernible] and others have shown that particular touch point in that sort of 13 to 18 [indiscernible] -- really does stratify for patients who are most likely [ to sino ] convert from being asymptomatic to symptomatic. So that's what's being used for the asymptomatic cohort. But really, it's a symptomatic cohort that is driving the powering assumptions in the study and where we expect to see the biggest future. And you may recall that one of the slides shown by Dr. Rohrer, was one from GENFI that showed a very nice drop-off in CDR-NACC-FTLD in patients that have been followed particularly in that 0.5 to 1 and 1 to 2 range. So that's the patient population we'll put most focused on.

Got it. Fantastic. And do you think that this GENFI data that will help you add a little bit more context to the patient population? And do you think that, that would also be important if some of the biomarker data is not necessarily consistent if you see some variability, let's say, in the neurofilament data?

Absolutely. And this is our way of really making sense of this data set in a way that allowed for some kind of synthetic control, right? And I think it's a statistically valid method of comparing and contrasting data and with all of the carriers, which we've already been pretty transparent about. And I just think that in the absence of having a placebo group, this is a great way to really look at what a longitudinal cohort that has been well followed and studied that is very similar in nature and character to the symptomatic cohort we followed in the Phase II could show. And so I think, again, looking for trends would be important. And the 2 populations in and of themselves are very used -- will provide useful clues. Now as it relates to the rest to the biomarkers, GENFI did not measure or complement all lysosomal projects. Or I think if they did, they haven't actually published that data. They measure neurofilament. So we can look at that, what was neurofilament levels at 12 months. So that will be another interesting competitor. So whatever we could compare in the same matched control, we will. But we're measuring a lot of biomarkers, so not all of them are comparable. So yes, it should be a rely interesting data set.

Yes, Shehnaaz, I just wanted to follow up on that. When you look at the GENFI database. And also, I'm sure in your data mining, are there themes in some of the more rapidly progressing FTD patients that you see on biomarkers? In other words, do you see more engagement with neurofilament or even other markers of, say, inflammation or something of that nature? I don't know if they're -- If there are some commonalities in patients that are fast progressors versus slower progressors either in your own data or in the GENFI database?

Yes. It's an absolutely great question. And the long and short of it is we don't really understand whether -- we don't know enough about the data set in order to really know whether we're seeing those correlations. Our goal would be to really look at that over time. And in the Phase III, in particular, be more intentional about the way we do some statistical analysis around those associations. So it's a bit too soon to tell, I would say.

Got you. And then from the regulatory engagement, I think that's probably the next step after you do the biomarker analysis and have a little bit more mature data that they'll have more confidence in using some of these in clinical design, is that fair?

Yes. I mean I think, again, we have to -- we don't have an interim analysis planned in Phase III, which means that we're really collecting the entire data set and then speaking to regulators at the end of the study. when we have retrospectively done some of that correlation analysis to determine, again, what the total picture looks like as opposed to relying solely on CDR-NACC-FTLD. So that will come at the end of Phase III because we don't have an interim analysis in the Phase III. And should there be an issue or should we not see the kind of change we're hoping to see in the CDR-NACC-FTLD then we can rely on that -- to those other biomarkers, again, to look -- to tell a more complete story about what's going on and to look for an approval based on the totality of the data, much in the way aducanumab did. So that would be our pullback plan. Our plan right now is to show a change in the CDR-NACC-FTLD and we powered the study appropriately to do so.

Yes. Got you. Okay. Yes, that's my next question was, if we look at the biomarkers and the trends that you'll see in the FTD program with 001. What are some of the learnings that you could make in Alzheimer's? Does that same GENFI database or some of your own work in Alzheimer's show something that further validates the totality of the platform?

Yes. Again, I think it's too early to tell, Geoff. I think what we'd like to do, we can do this with TREM2 more readily than we can with the FTD program because it's already in a pivotal study. But with TREM2, for example, what we're doing is looking at both carriers and noncarriers that will be enrolled in the current Phase II. And we will do a retrospective analysis of carriers versus noncarriers as it relates to, again, the CDR-SOB in this case. and look to be able to stratify the patient population for Phase III. So there, we can use soluble TREM2 as a predictive biomarker potentially to help enhance the stratification of the pivotal studies in AD. Similarly, we could look at other markers of microglia activation, and we've talked about some of those, CSF1R and Osteopontin and others that clearly show that microglia have been activated and do some second order analysis, beyond TREM2 to determine whether or not this is correlated with the change in CDR, some of what what we see. So that can be done and will be done at the end of Phase II, and that will hopefully set us up nicely for the Phase III design.

Got you. That's helpful. Yes. I mean I think when we talked a while ago when you guys were first developing both the entire platform, it's always in the backdrop of having beta amyloid and tau and AD being the sort of standard biomarkers. And would you say that the approval of adu, does that add more complexity having to consider patients that perhaps are adu-experienced or donanemab-experienced down the road that they may engage the pathway and have more of a immuno response, right, neurological response to those drugs. It's not like cancer where you have resistance mechanisms, but you may put a patient down a certain pathway that has experience with the beta amyloid antibody?

Yes. I think I mean the verdict's still out on whether or not something -- aducanumab becomes the standard of care per se. So I think we'll have to see how that plays out. The reality is that there's still likely to be many patients that -- I would say it will be interesting to see how far the active spend penetration goes. So I think the question of is it standard of care or not, is one question. The other is as you pointed out, if it's background therapy, what immuno neurologically mediated response to treatment can you expect? I mean our view of it scientifically is that -- there shouldn't be too much crosstalk between inhibiting amyloid and what you would expect to see with microglia activation, I mean in a negative way. If anything, there should be positive synergies because one of the key functions microglia, of course, is phagocytosis of pathological protein. So I think in addition to vascular health and maintaining synaptic connections and the interplay between oligos and other cells. So I think our perspective is it should all be positive from the point of view of therapeutic synergy. I think the other question is on side effects, the side effect profile and what is the likely interaction going to be there? So I think -- sorry, now we're talking about TREM2 in the context of AD, which is also a risk factor for Alien -- also upregulate microglia. So I think there, too, it becomes a question of what kind of risk benefit will you end up being? And patients that are on background therapy more likely to have a narrower therapeutic window than you would otherwise expect. And I think the verdict is out. We'll have to wait and see.

Yes. That's true. And ARIA may add some complexity to it. as well, to your point on side effects. Although I think with adu the ARIA rate wasn't really that high relative to other beta amyloid antibodies?

Right. And I mean as you know there's is a school of thought out there that if you receive ARIA, you're a -- it really is a surrogate marker of target engagement. So as it's going to be a question of just what is the real therapeutic window, and combination of studies will have to be conducted to clearly determine, what is the true kind of translatability of maybe an immunological phenotype into a clinical phenotype and additional risk. But I think we're ways off from knowing that. And -- at least our current view based on kind of immune checkpoint hypothesis is that these are clearly risk factors that are well associated, particularly TREM2, which is a very well-validated target. We also know in the triple transgenic model that you see that in the absence of TREM2, you have kind of more amyloid deposition and tau pathology. And so we really do think that you should see an enhanced therapeutic effect based on what we know about the biology. But obviously -- and the fact that the therapeutic threshold for [ FTD ] is still pretty low, roughly a 20% change suggest that there's plenty of opportunity to add on.

Yes. No, I agree with that. And I would say, too, that we've talked a lot about beta amyloid and adu approval on a surrogate. But we haven't talked about tau as much. And I thought that was some of the novel components of donanemab and try to get rid of patients that were too severe or not severe enough to try to maximize the benefit in patients that are more likely to respond. Do you see the same effect here with TREM2 in your studies? Is that something -- is that sort of gating of patients, something that you guys believe in through tau as well? Or is the jury still out on that?

I think the jury is still out. I mean our trial is looking at primarily early AD, based on just sort of conventional wisdom and where the field has gone to in terms of intervening earlier, giving you a better chance of actually being able to inhibit progression of the disease or at least stabilization. So -- but it is an all-comers patient population with early AD. And the goal is to really, again, stratify in our case by TREM2 to carriers versus not and determine whether that's where we're seeing the primary clinical benefit. And we do expect that both -- again, that an all-comers population will benefit, again, because it's based on microglial activations and the effects that we know this will have on potentially enabling better removal of either amyloid or tau pathology. But I think again, it's too early to tell exactly how that's all going to play out.

But wouldn't you say though that the enthusiasm is there for in their degeneration now based on last week's approval. I mean maybe enrollment time lines for some of your -- for all of your programs really could be moved out if there are more engagement among neurologists, both in the academic and those in the community setting that run studies?

Yes. There's no question. And I think if we move to sort of a cooperative model where we're doing these trials, with combination therapies, particularly sooner rather than later, there's certainly an opportunity to pull [ fast ] approval. And as you alluded to, there is also the opportunity to do maybe a single pivotal and try and file on biomarkers plus tough economics of endpoints. So I don't doubt that those opportunities exist, meaning our main opportunity to engage with FDA will be at our -- in the Phase II meeting. And so that's really the opportunity to push the envelope, I think, in terms of what's required. So we'll very much look forward to doing that. And as I said, in FTD too, the engagement with the agency, which has been very positive, has really focused on collecting the totality of the data set and then having a discussion about whether it's sufficient for approval independent of whether we've shown a change on the cognitive endpoint.

Got you. That's helpful. Well, let's switch gears to ALS. Maybe just give us kind of the lay of the land in that program? Where you guys are? And what are the next sort of data points that we could look forward to?

Certainly. So we've outlined -- we talked a little bit, I think, on the [ new ] slide set that about an expansion indication strategy for the progranulin franchise. And the franchise is really AL001, the lead program in FTD, which is an IV formulation as well as AL101 which is a potential subcutaneous formulation, which can be developed for broader indications like Alzheimer's and Parkinson's. On the AL001 front, the next place to go, we think, is ALS because TDP-43 pathologies are well described as a primary sort of inclusion body which is seen at autopsy in these patients. We also know that C9orf72 mutations can be found in the ALS patient population. You might recall that the other 2 cohorts in the Phase II open-label study right now on asymptomatic cohort, and the C9orf72 cohort for FTD. So it's possible that there'll be some read-through from C9orf72 cohort, which will inform how patients are responding. But notwithstanding that, we believe that we have sufficient biologic rationale to initiate a Phase II study in ALS, which will start in Q3. We've already have a protocol that is ready to go. And what will be is a small signal-seeking study, proof of activity study, if you like, in ALS patients. And we'll look at the ALSFRS, which is the cognitive endpoint in ALS as well as other biomarkers. So again, just looking at markers of microglial activation. And that will be sort of the basis for determining whether or not to enter into a more formal either Phase III or Phase II/III pivotal study. So the goal is again to go with the biology is strongest, and do some at least an initial signal-seeking study. Couple that with the data readout that we might get from the C9orf FTD patient population where there may be some read-through and then determine what the registrational path either as a single pivotal or joint Phase II/III study might look like.

Yes. And just along those lines, when you look at progranulin as well as microglial engagement in diseases like ALS or Huntington's. It's -- that's not where you guys went first, but is there still evidence that, that is -- plays a role in disease pathology. And is it the same mechanism that you think in early in the disease development? Or is this sort of a middle stage?

Yes. So we think it is the same mechanism and it is sort of middle stage because I think that's where, again, we see the pathology most manifest based on autopsy. And also, there's a lot of -- a fair amount of genetic data that seems to suggest that C9orf patients do, in fact, have comorbid ALS. And so that's really the data that informed our desire to go into Phase II. We also have some in vivo data that is interesting. So the combination of, I would say, the biologic hypothesis has been strong. The in vivo data and the strong genetics data underpinning what's happening with TDP-43 pathology, was the reason to go forward. And I think, again, our strategy of doing early signal-seeking studies to validate the underlying biologic hypothesis is the way that we felt it was appropriate. And we're working with the NEALS Consortium to run that study, which is a pretty rapid and efficient way to determine whether you are seeing an effect.

Got it. Can you speak a little bit about the challenges you've had to overcome to develop a subcutaneous version of AL001 or AL101, I should say?

Right. So AL101 is currently in a PK/PD study, and we'll show some of that data later this year. And what we've done is actually looked at different IV dose levels and subcutaneous dose levels and look for bioequivalent. And so we'll show you some of it this year but I think, the bulk of it next year. We were doing the appropriate studies there to look for the appropriate exposure on the subcu doses as what you would expect in IV and we're quite encouraged by what we see. And of course, the opportunity to have a subcutaneous formulation has a lot of advantages from a life cycle perspective and also gives us again the opportunity to differentiate the franchise based on faster market orphan indications for which you can charge premium prices, orphan drug like pricing versus a different formulation in Alzheimer's and Parkinson's, which will be, I guess, aducanumab like pricing, if you like.

Yes, understand. So with this dosing paradigm, will you be able to change where you actually administer meaning would you be able to potentially administer at home some of these patients? And how will that affect the paradigm?

Yes. So these go through different channels, as you probably are aware, Medicare Part B versus Medicare Part C which creates a clear precedent for the way that we would commercialize these. I think there lots of opportunities for subcutaneous formulations to be administered at home, particularly if, as a life cycle planning strategy, there is an auto-injector associated with the molecule. And again, it depends on the dose. So there is a limitation in terms o what is feasible. But typically, what happens is that you launch with the pre-filled syringe with a view to developing an auto-injector as a life cycle option, and that's the opportunity to really drive home, staff administered options for patients with AD and PD. And so that's the ultimate goal. We're at the initial stages of figuring all of that out, as I'm sure you can imagine. And so having a subcu data in hand, finding an equivalent dose that we think gives us the appropriate exposure is the starting point. And at some point in -- soon after that, we'll be looking to determine what is the right proof-of-activity or proof-of-concept study to test that in AD and PD.

What considerations go into deciding what a proof-of-activity study you're going to undertake?

So biomarkers are a big part of that. And I think in [indiscernible], it depends on the targets. So for example, with SIGLEC 3, our other immune checkpoint program, we'll be looking at CD33 as a key biomarker as well as other markers of microglial activation. And as mentioned some of the CSF1R, Osteopontin, soluble TREM2 all great and validated markers of microglial activation. So I think certainly the biomarkers. And then the question really becomes how much -- how -- to what level are you powering the study for efficacy? And that is really a question about [ alpha ] spend whether it's p equals 0.05 or some other 0.2 or whatever you think is appropriate for that initial study. And what you can learn from that study to then apply to the Phase III, the subsequent Phase III. I mean the emphasis will continue to be on biomarkers and I think both soluble plasma as well as CSF biomarkers, and that's where we're spending our time. We are looking at a number of biomarkers through the Thermoscan platform, which enables us to develop a view of the protein signature of these diseases and to determine what upregulated or downregulated at baseline. We then follow those patients and remeasure all of those proteins and then look at them in validated quantitative assays that allow us to perform statistics on the proteins that are signaling. And then at that point, we're able to then continue to validate that with our views of the literature and what we know about the underlying biology to determine that these, in fact, are biomarkers that are predictive of the disease. So that's kind of our methodological approach, and that's why you heard in the conversation last week that we've selected sort of 5 categories of biomarkers with examples in each that have been subject to that degree of rigor to really help us pinpoint what's truly reflective of the underlying pathophysiology. And that is a similar approach that we will continue to propagate in Alzheimer’s disease and Parkinson's and in the other neurodegenerative diseases which we choose to study.

Shehnaaz, just a follow-up on that. I mean there are lots of biomarkers in neurodegeneration overall. I mean, CSF is, I guess, somewhat fairly invasive, but imaging more and more has become the tech, and there aren't a lot of blood-based biomarkers that you can do. I mean how do you select the proper biomarker that made down the road, help you from a commercial perspective or a pivotal trial perspective that I'm just trying to think of how do you truly apply some of these biomarkers in the real world?

Yes. It's a really good question. And I mean, to be honest, some of it is emerging as our understanding of the underlying disease biology emerges. So in FTD, for example, it's well known that lysosomal function is a key pathological phenotype of the disease, your lysosomes which don't function your progranulin does not signal appropriately, and there is a 100% penetrant with the deficiency in progranulin clearly correlated in haploid-insufficient patients to FTD. So I think there, you've got a clear marker that lysosomal function is important and then the question becomes, well, which markers of lysosomal function should we be looking at. And this is where the field and literature can be quite useful in terms of pinpointing, for example, the [indiscernible]. And then it's a question of zeroing in on, okay, which [indiscernible] matter and why do they matter? And is there biologic elevations for this? And are we seeing in the longitudinal follow-up of patients at 0 month, at 6 months and at 12 months changes in these markers of lysosomal function and do they make sense. And so I think there is some scientific intuition that goes into the initial selection of what's important in the context of the disease. But then ultimately, that needs to be validated through statistical rigor and seeing the same trends play out in different data sets. And that's really the approach that we've used. I mean TREM2, for example, I think, is people sort of knew that it was a really interesting target in the context of AD neurodegeneration. Because of the GWAS data that has been developed and because of its proximity to ApoE, which is, of course, a well-known risk factor in all that is. But I think only recently have we seen some more publications in transgenic mice and in triple knockouts and that begin to unpack more closely. Well, what is the role of TREM2 as it relates to A-beta and Tau. And so I think you start with a valid biologic hypothesis. And then as more and more data set start to develop, you develop ultimately more confidence in it and generate your own data sets as we are in FTD, and sort of put a stake in the ground around what we think is valid or not. And that's really what we're trying to do. And again, FDA being open to that sort of approach, is incredibly encouraging.

Is there any sort of sales process, I would say, to help recruit the academic community? I mean you want to have presentations at various neuroscience conferences that talk about biomarkers and to get people thinking more about TREM2? And do you have to talk to companies to say, why don't you evaluate this marker in your study? I'm just trying to think of ways to maximize the -- let's say, the visibility of your biomarkers?

Yes. So I mean that's a great question. So I'd say the 2 most obvious places to start are the registries, right, the GENFI and all FTD registry in which These patients have been followed up for 5 and up to 8 years with annual assessments of both plasma and in some cases, CSF biomarkers. And we have the theorem in the GENFI cohort. And so all of these biomarkers can be tested retrospectively in those patient samples. So that's just a great way. As soon as they publish more of these -- so it's sort of a collaborative effort in the sense that we put a stake in the ground around what we think is relevant in FTD based on our data sets. And then there's sort of a look back at the GENFI cohorts and looking at those [ same ] biomarkers to determine what it looks like in a longitudinal cohort of patients. So that's a very valid way of trying to again narrow down into what's truly relevant for both diagnostic and prognostic reasons. So I'd say that's the most helpful way to do it. And then to the Bluefield project, companies that come together and are looking, for example, at neurofilament quite intently and trying to unpack some of the different trends and indeed find associations between levels of neurofilament changes in FTD and trying to provide a more robust cross-functional cross-company collaborative view of what's the time point over which to expect changes, what are the levels of changes, what's meaningful and whatnot? And then ultimately, leading to, can we correlate those changes with clinical outcomes. So that effort is already well underway in FTD. But certainly, there's an opportunity to replicate that in diseases such as Alzheimer's and Parkinson's.

And I'm assuming that you're in the case of AbbVie, your partner companies are okay with this process. They don't want to keep anything proprietary and kind of on the DL until it's more validated? Or is there a trend?

Yes. I would say there's a trend towards more collaboration and certainly sharing data and information more broadly. I mean when you get into patient samples and that kind of thing, obviously, there are more privacy lower than things that govern the ability to do that. But we're very fortunate because in the design of our Phase III for FTD, we actually were able to benefit from data provided by GENFI and impact primary data. And so we use that data to help model the assumptions for our Phase III in the rate of decline that could be expected. So it was actually based on real data. So there's a fair amount of cooperation that's already happening.

I got you. That's helpful. And just the last couple of minutes, maybe more of a sort of higher-level questions on strategy. So from a financing perspective, you guys don't necessarily need any sort of biotech or pharma partner to validate anything. You've done it yourself. But in terms of nondilutive sources of funding, are there some of those available to you? How are you thinking about that? And from a partnership perspective, do you want to keep the FTD program, for example, as long as possible? Or is there a thought that you may need down the road a commercial partner?

Yes. Well, I think we've proven that we can execute quite well. I mean we went from preclinical to Phase III in a matter of, I think, 2 years on the FTD program, which must be some kind of record. But -- and so I think we feel quite comfortable that we could go into proof-of-activity and proof-of-concept studies and certainly pivotal studies in orphan indications. As it relates to Alzheimer's and Parkinson's, the trend, as you know, has been to partner those out because there are such large studies and pretty expensive. So cost sharing and risk sharing makes sense there. So we're thinking through all of these and keeping all of our options open.

Got you. That's helpful. Yes. And when you think about bringing other -- bringing in new assets and new mechanisms in, is there an appetite for that based on what you've seen in the literature or at various medical meetings, maybe pathways that are somewhat peripheral to yours? Or is that -- do you want to derisk what you have a little bit further today?

We have such a large pipeline, more stuff than we can have the time and money to work on. And one of the great things about having on as the scientific [indiscernible] is that he has 40 years of experience in generating great targets. So I think we're actually very excited about our own pipeline. I mean the next really interesting target is MS4A4A, which is a master regulator of microglia sort of upstream of TREM2 and very, very -- in the TREM2 parkway and very, very -- a very, very exciting target. And behind that, we have several other risk genes that have been clearly identified and with single-cell gene sequencing and a lot of these other modalities, we feel like we have a treasure trove of research targets that we can continue to propagate, we don't feel the need to go outside of that. From a company diversification perspective, we've got our IL pipeline, which is coming along nicely. And we're always thinking about other potential modalities outside of antibodies that could be useful in certain CNS monogenic orphan open situations that might lead us down the path of looking beyond antibodies. But for now, we think we have plenty to do in-house, so no need to look outside.

And so the most of the newer investments are mostly for clinical and bench scientists, Is that fair?

Yes, absolutely. And I think really focused on that translational space. So what we've done really well is move things from research into the clinic really fast. And so that's the model. It's to continue to really accelerate targets from research into early proof-of-activity studies, determine whether we -- signal-seeking studies and then decide to make bigger investments following that.

Perfect. Well, with that Shehnaaz, we're getting close. So thanks a lot for the time. This is really helpful conversation. And again, next year, Napa for real.

Don't need to ask us twice. Thank you for having us.

All right. Thank you.