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

So good morning, everybody, and thank you for attending Citi's 16th Annual Biopharma Conference. I'm Neena Bitritto-Garg, I'm one of the biotech analysts here at Citi, if you don't already know me. For our next session, I'm really pleased to be joined this morning by the CEOs of 3 companies working in the neurodegenerative disease space, including Arnon Rosenthal, from Alector; Bruce Goldsmith from Passage Bio; and Gene Kinney from Prothena. So we're going to cover some emerging topics kind of on the outlook neurodegenerative disease, R&D at a high level and then some indication and company-specific questions as well. And if anybody listening to the webcast has questions as we go through the discussion you can feel free to e-mail me directly or you can submit questions through the online portal and they'll come to me and I'll try and incorporate them as time permits. So I just want to start off by turning it over to all of you to kind of give some opening remarks. Maybe we can go alphabetically, I guess, so we can start with maybe Arnon, if you want to start, then Bruce and then Gene.

Good morning, everyone. I'm Arnon Rosenthal, CEO and Co-Founder of Alector. At Alector, we are using sort of an alternative strategy to develop drugs for dementia neurodegeneration, instead of going after misfolded proteins like beta and Tau, we are recruiting the brain immune system to counteract multiple disease pathologies. So conceptually, we are very similar to immuno-oncology. In immuno-oncology, people switch from trying to kill the tumor directly with the radiation of chemotherapy to recruiting T cells to counteract the tumors. We are doing the exact same thing. We are really recruiting the brain immune system to counteract neurodegeneration. So all our drugs are practically immune checkpoints for the brain immune system. And by next year, we will have 10 clinical trials going with 6 different drugs in 6 different indications.

Great. Thanks very much. Following up on that, Passage Bio is using a very specific approach, which is using gene therapy, and in collaboration with Jim Wilson and the Gene Therapy Program at University of Pennsylvania, to address patients with central nervous system diseases that are either monogenic or in the future, hopefully, non-monogenic as well. And this includes both pediatric and adult targeted indications. The idea is that the collaboration with the gene therapy program, and Jim's extensive group that has worked the evolving in both manufacturing and novel capsids, all the way through IND-enabling studies and animal models is that Jim in collaboration with us designs the preclinical strategies to move programs forward, and then we execute on the clinical manufacturing and then ultimately commercial strategies. We currently have 3 programs in the clinic that address 2 pediatric disorders, which are lysosomal storage diseases and 1 adult disorder, which is frontotemporal dementia, which we might get into a little bit of a conversation about. And we've recently also expanded our collaboration to focus on non-monogenic diseases, including Alzheimer's and temporal lobe epilepsy. So overall, the company, which is based in Philadelphia close to where Jim's lab are is focused on clinical development, manufacturing and as I said, ultimately, commercialization. And the overall programs that we hope to advance are all focused on CNS disorders. So thanks very much, Neena.

I guess I'll wrap up by saying thank you again for having me on the panel. It's great to be on with such esteemed colleagues here. So my name is Gene Kinney. I'm the CEO of Prothena. Prothena is founded on the scientific heritage, originally some of the original developments by Dale Schenk and his colleagues, starting to understand how proteins dysregulate in the context of disease first in the context of central nervous system disorders, also in the context of peripheral misfolded protein disorders like AL amyloidosis, ATTR amyloidosis. How to intervene in that process? How to make sure we target those proteins correctly to ameliorate their biological toxicity? And then how do we design in the right components and mechanisms to make sure that we can clear those proteins from the affected organs and/or neutralize their toxicity. So based on that founding scientific principles, Prothena has developed a fulsome portfolio ranging from Phase III assets through to new entrants into the clinical space designed to address diseases caused by misfolded proteins, including those in the periphery such as the peripheral amyloid diseases as well as in the central nervous system, where we focus on Alzheimer's, Parkinson's and other central nervous system disorders.

Excellent. So I want to start off by kind of talking about some general topics within the neurodegenerative disease space. And -- now obviously, kind of the first question here is around the recent approval of aducanumab. I personally have been getting a lot more interest from investors just around the broad CNS space. post the approval. So if we could just talk a little bit about and expect to get thoughts from each of you kind of around the implications of that approval kind of on the clinical development pathway and the regulatory kind of hurdles around kind of developing neurodegenerative disease drugs overall. And how the approval in your view, impacts your individual programs? Everyone -- maybe we'll go the reverse order this time. May be Gene, if you want to start and then Bruce.

Perfect, and polite panel, I like it. So yes, so it's a great question, Neena. I think in our minds, without a doubt, the accelerated approval around aducanumab has sparked interest both from an investor perspective as well as from a strategic perspective in the neuroscience space. And as we step back from the space and maybe some of the controversies around that approval, I think the idea of moving from a disease space where all of the available treatments were symptomatic in nature, didn't really address the underlying pathophysiological progression of the disease to now a first agent that's actually designed to address that underlying pathophysiology is really quite a remarkable statement for the field of neuroscience in general. And I think over and above just that statement by itself, there's a clear clinical and now, regulatory pathway for approval of such treatments. And potentially even a recognition of the need and the unmet need in the space through the accelerated approval mechanism. And so I think overall, it's certainly been a positive, I think, for those of us developing therapeutics in the space. It provides a lot of data for us to look at in terms of how we think about clinical trial design, how we think about inclusion exclusion criteria for patients, clinical assessment scales, what are most appropriate, with which to actually address change over time in the time course that's reasonable for the observation period of a clinical study. And so I think there's been a lot of progress in this space about what works, what doesn't work. And obviously, as a field we learn from each other. And I would just point and then I'll stop talking here to the progress really even just between the clinical designs around the aducanumab EMERGE and ENGAGE studies to some further iterations and improvements that we saw with the Eli Lilly TRAILBLAZER study, where they improved further on patient selection criteria by the inclusion of tau PET imaging at baseline and then introduced a new clinical assessment to the iADRS endpoint, where I think that was a further refinement in terms of signal fidelity over a shorter period of time, allowing for shorter trials, potentially less expensive trials in order to establish proof of concept moving away from, say, CDR Sum of Boxes and towards that iADRS endpoint. So very exciting to see the field move along the clinical and regulatory side in the way that it has even over the last 6 months.

Yes. And I guess just to add to that, a very comprehensive review, and I think great comments. I think one of the challenges is exactly what Gene was talking about, which is how do you start to incorporate baseline measurements of imaging or other biomarkers. And I know we'll probably talk about some of them today, into establishing surrogate markers that are all moving in the same direction, for example, and increase the likelihood of clinical benefit at the end of the day. And the other question, I think, that comes up is what is the clinical benefit that you're looking for because when you start to look -- and can you apply some of the learnings from Alzheimer's disease to ALS and Parkinson's and then expand this idea of accelerated approval, not just for imaging in Alzheimer's, but also for other surrogate endpoints and accelerated approval pathway more broadly. I think not to focus on the potential negatives or downsides, I think one of the challenges that we may experience as a field is how do we then address emerging therapies that have some potential benefit and incorporate that into clinical designs, are we looking at failures? Are we looking at nonresponders? What are we looking at from -- or are we looking at our combination strategies? And I spent a long time in oncology where that's often the strategy as you start to think about how the approval landscape is going to change, and is the patient population that you're addressing going to be different somehow than you started with. So these are some of the challenges. And I think that leads into the third point I wanted to make, which is subsets of patients. And Gene mentioned this as well, which is looking at entry criteria or definitions of subsets of patients and not just simply the gross evaluation of symptomatic and certain levels of progression, but are there other markers that come along with those populations that we can then look at for potentially faster approvals and faster benefit or potentially that wouldn't be appropriate to treat with aducanumab. So those are, I think, some of the emerging questions that we, as a field, need to address.

Great comments. Yes, I think that the main -- for me, the main revolution in the approval of aducanumab is that the FDA indicated that they are going to look at the totality of the data. I mean I think until then, basically the clinical endpoints were the only measure for drug efficacy and the clinical endpoint for dementia and neurodegenerations are terrible, means they are really still primitive. They are very noisy. They require large clinical trials, long clinical trials. And I think that the FDI messaged that they are going to look both at the biochemistry and clinical end point together. And they basically factor the biochemical mechanism as part of the drug approval process, I think, is really transformative. And I hope that they would stay this course because this could really transform neurodegeneration. The right-limiting stage in neurodegeneration is really the clinical trials with really the outdated clinical endpoints and really moving to supplement these clinical endpoints with biomarkers, rational biomarkers. Means that really reflect disease and would really transform sort of the interest in neurodegeneration, the cost and sort of the number of trough drugs that will be tried in the clinic. So I think that that's really a significant message. And I hope that the backlash against sort of the approval of the aducanumab will not change the FDA view that sort of -- what we understand the disease is much better now. We have a much better handle on biomarkers now on imaging, and that the totality of the data is the right approach for drug approval.

Absolutely. Yes. So kind of on that point, obviously, as all 3 of you know, there's a lot of debate going on right now in the scientific community and also in the investor community kind of a round of biomarkers in neurodegenerative disease studies. And I think specifically around the difference between some of these kind of nonspecific, so like indication nonspecific biomarkers of neurodegeneration versus the more specific biomarkers like in Alzheimer's amyloid. So I guess, how are you thinking about that concept and kind of translatability of these maybe less specific biomarkers into kind of something that is reasonably likely to predict a clinical benefit, right? Like how should we think about translation of broad markers of neurodegeneration into clinical benefit?

Since we're going in a order maybe I'm the first one this time, I'll jump in. Sorry, Gene, I'm trying to keep it polite. So I think the answer is -- and I hate this and love it, but it depends. And I think it really depends on a series of issues, and we've seen this in the field, and we've seen this with, for example, neurofilament light, which is one of the generalized markers that I think has been an area of focus for many, many companies. The issue with generalized markers is that we're at the cutting edge of understanding pharmacodynamics of those markers, stability of those markers, how therapeutic benefit is linked or delinked to those markers and why. And so it really is a challenge as we're at the cutting edge of treating some of these diseases. So we may talk about frontotemporal dementia. There's a great -- there's an emerging series of data on natural history of neurofilament light and -- sorry, neurofilament and frontotemporal dementia, which gives us some book to hang our data on to say this is likely to be indicative. But in fact, as we do therapeutic interventions, we really don't know what the outcomes will be because we don't have enough interventional history to say this is likely or unlikely to predict outcomes. And I think we've seen some emerging data that disconnects neurofilament light levels from potential therapeutic outcomes and others such as contrast MRI or other measures that seem to link. And I don't want to steal anybody's thunder on the panel. But I think that's really important to put in context. And I could -- the pediatric diseases, which we're addressing, which are even more rare and less studied. We get asked a lot about how are you going to predict not only the [Indiscernible], these are as a replacement with gene therapy, what is the level that you need? And then what are the downstream biomarkers, what are the time courses? And the answer is we have a little bit of natural history to suggest what happens in certain disease sets, but we actually don't know yet clinically what the intervention will do on all of these different areas. So part of this measure is that it really depends on how much data we have, how much interventions have changed the clinical course. And therefore, what we know then about the biomarkers. So this is really -- we are at the -- the 3 of us and other companies in the field are at a cutting edge of really understanding the correlation between the various biomarkers that are either general or specific to the disease and how those respond to various therapeutic interventions. And I think we're all trying to avoid having to wait for years of clinical outcome when a therapeutic could have significant benefit to either a child or adult early and how do you balance that risk benefit. And it may come down to exactly that, which is what's the safety profile, what's the risk versus what's the potential benefit here versus the cost of waiting. And so I think that's where we kind of see the biomarkers evolving over time as important to explore and then important to correlate to outcomes. So I'll stop there. Hopefully, I haven't exhausted Gene and Arnon on the topic.

That's great. Yes, I think that biomarkers is an evolving field, but I think it has a tremendous potential and it's rapidly getting better as we understand disease mechanism, as we understand the relations between different biomarkers and disease outcome. So I think biomarkers is the future of neurodegeneration. I hope that the clinical endpoint will be improved with digital health with continuous monitoring of cognition and movement. But in parallel to the improvement of the clinical endpoint, I think that biomarkers that really reflects disease progression would really give us significant handle on the disease. Even if they are not approved by the FDA, I think they will allow companies to tell which of their 3 drugs is the drug that was advancing. And I think this will make clinical trials much cheaper. And again, people will be willing to take more risk instead of investing $1 billion in an Alzheimer's drug before knowing if it's working, you can do a small trial, see if one of your sort of biomarkers that you trust is sort of reading out and then advance the drug that looks good. It means we are routinely measuring 5,000 or 7,000 biomarkers now in the CSF of patients, looking at disease progressing, looking at the effects of drugs and obviously, drugs that impact this sort of a larger subset of these biomarkers is -- gets the priority it needs. I think that every disease is sort of fundamentally has biochemical readout means that's what I call a disease signatures, has a panel of proteins that are abnormally up-regulated or down-regulated and if you are able to change this directionalities, you'll have -- you're more likely to have an effective drug. So I really think that, again, there are individual biomarkers like Neurofilament that we don't fully understand how it -- what will happen? When will it happen? Even imaging, we are not sure the time course. But in totality, I think if we look at enough biomarkers, we will find biomarkers that really reflect disease progression and drug effect. And I think this is where the field is and should be moving.

Yes. I think it's been well said. I mean I would maybe just to expand a little bit. We really think about biomarkers almost in a fit-for-purpose way, right? I mean, so we talked earlier about the use of biomarkers for inclusion excursion. How do we select patients that are most likely to respond to the biochemical pathway that we're manipulating in terms of our treatment, right? And I think that's an important use of biomarkers. I think in this conversation, we're talking about the potential use of biomarkers from a disease progression perspective. Is there a biomarker that we can reliably look at to understand if we're having an interventional effect on a disease process that we understand to some extent. And of course, then there's the regulatory requirement, right, is a biomarker following intervention reasonably likely to predict positive clinical outcome, which is yet another level. And I think we have to put these different biomarkers in different categories. The place that we've seen, the use of biomarkers coming back to the [Indiscernible] experience is now on that accelerated approval. And I think there were 80 some pages of explanation around that, that the FDA put out. And it was clear that it wasn't just about that biomarker movement. There were other things that were compelling to the FDA in that moment, the clinical outcomes and how they track with the biomarker movement, the size of the safety database, which is something that I think has already been discussed. And so I think it is the totality impact of that package that ultimately is going to matter from a risk/benefit perspective as we think about the use of biomarkers for potential accelerated approval pathways. As the other panelists have said, I think that's appropriate. I think these diseases are serious and severe. Alzheimer's disease was the sixth leading cause of death. Last year, the societal burden is enormous. And treating that seriously and making sure that we avail ourselves of all regulatory pathways, I think, not only makes sense, but is responsible.

Absolutely. No, that makes sense. So now I want to talk a little bit about some specific indications. I may come back at the end to talk about some more general topics. But maybe let's start with Alzheimer's disease, since that is an indication that all 3 of you do have programs in. So I guess if I could get kind of from each of you a summary of the approach that you're taking kind of to address Alzheimer's disease. And then also at a higher level, what ultimately is -- can your philosophy on the type of therapy that it may take to deliver a meaningful kind of treatment effect to patients. I mean do we need to have different therapies for different patient subsets. Do we need combination therapies? Do you need different treatment modalities. I guess, how are you thinking about those sorts of things? And whatever order you guys want to go it is fine.

Shall I start?

Got for it.

Yes. So basically, we are relying on human genetics to develop drugs for Alzheimer's disease and the surprising finding of the genetic pho sporadic Alzheimer's disease was that the majority of the risk genes for Alzheimer's disease turn out to be genes that control the brain immune system. And the second surprise was that the mutations in these genes are mutations that weakens that decrease the activity of the immune system. Until then, many people thought that Alzheimer's is actually a form of an autoimmune disease that you actually have to suppress the immune system in order to elicit therapeutics. But the human genetics told us that the immune system plays a key role in the disease and that you actually have to enhance or strengthen the immune system to counteract the pathology. And biologically, what we know about the brain immune system is that not only they are the garbage collector of the brain, they really contain all the misfolded proteins. They also contain multiple other pathologies that control the blood-brain barrier integrity, they control any type of vascular blood leakage. They control the myelin resurfacing. They control the astrocytes that are the main supporters for neurons. So we think that the micro -- the immune cells in the brain set are called microglia, are really the control system of the brain. And if they stop functioning because of aging or genetic mutations, a lot of random pathologies emerge. So basically, our drugs really target the immune system in the brain, they target genetic risks for Alzheimer's disease, and they really counteract the genetic risks. If there is a certain gene whose loss of function cause the disease, we develop a drug that functionally enhance the function of this gene. And this is a case, for example, for our TREM2 drug, TREM2 loss of function mutations lead to Alzheimer's disease. So we have a biologic drugs that activate TREM2 and by this increase the survival, proliferation and functionality of microglia. And in opposite cases where overexpression of a certain protein cause the disease. We block this protein, and this is the case in protein like SIGLEC 3 which is an inhibitory checkpoint molecule for microglia, who's overexpression lead to increase Alzheimer's risk. And in this case, we block -- functionally block this chain, very similar to what KEYTRUDA does for the PD-1 system. So again, we are really enhancing rejuvenating, recruiting the brain immune system as a therapy for Alzheimer's disease. And in the next year or 2, we will have 4 programs along this line in Alzheimer's disease. Our most advanced program is in Phase II with the TREM2 drug. Next year, we will have another Phase II drug with the SIGLEC 3. And we will have 2 additional Phase II drugs with other risk genes for the disease. And just -- I'm sorry, just one more thing, means combination could work very well. Our drugs enhance or rejuvenate the immune system in the brain. Drugs that target beta or tau or alpha synuclein really recruit the immune system to eliminate this misfolded protein. So a combination of a drug like aducanumab or anything that tag the misfolded proteins together with a drug that enhance the immune system could be synergistic. So combination therapy could work very well in this context.

So maybe, yes, just to expand a little bit. It's -- I think stealing one of Bruce's lines, I think it depends, right? It depends on the disease state. It depends on the patient population that you're targeting, how you think about this therapeutic. At Prothena, we focused on -- particularly in the field of Alzheimer's disease and the pathophysiological indicators and we think drivers of the disease. We are -- we have a long history, as I mentioned, that goes all the way back to Alan Pharmaceuticals and before that, Athena Neurosciences, really thinking about these misfolded proteins in the context of central nervous system disorders. Amyloid beta was one of the first areas that we studied extensively. We learned a lot about that field, not just from a basic biology perspective, but also from a clinical science perspective, and we're learning more, I think, every day. From a basic biology perspective, we feel like targeting these proteins in a very specific manner is important. You have to target them in the right place. We think the amino-terminus targeting approach for amyloid beta is appropriate. And as we saw molecules starting to advance through, I think, better clinical trial designs, we saw a need for a best-in-class approach with an anti-amyloid beta targeted approach. We have a molecule there that's wholly-owned within Prothena called PRX012, that's designed with that in mind. So it's approximately tenfold more potent in terms of how it interacts with amyloid beta, which allows us to think about subcutaneous formulation and delivery on a very convenient dosing schedule. We think, obviously, thinking about access and compliance that drives positive clinical outcomes. So we think that's an important advance for the field. As we move beyond that, we know that amyloid beta has an important modulating role, not only with the immune system and the inflammatory system in the brain, but also for the protein tau, which we know is important with respect to synaptic function in the context of Alzheimer's disease. So there, we have a molecule that is partnered with Bristol-Myers Squibb, that's recently initiated Phase I trials, we call that molecule PRX005. That molecule targets a very specific region within the microtubule binding domain of the tau protein. That at least in our hands, in the preclinical setting provides for a very consistent and robust biological beneficial outcome across a number of different preclinical models. And then ultimately, as Arnon indicated, we think combination approaches are ultimately where this field will move. In our case, we've developed an active vaccine strategy that combines what we feel is the appropriate targeting of both the amyloid beta and tau protein that active vaccination strategy has to solve a number of issues, not the least of which you're developing a equal or proportionally equal immune response to the 2 proteins, making sure that we're driving a good immune response in a typically elderly population and avoiding a cytotoxic T cell response to these endogenous proteins. We've recently shared some nonhuman primate data there. One of the things we're very excited about with that vaccine program, which is wholly owned by Prothena as well is that it provides us the opportunity to start thinking about combination approaches potentially even with neuro immunomodulatory approaches, but also to start to think about how we start moving this field from a treatment paradigm, treating patients already diagnosed with disease. Two patients that are predisposed to develop the clinical manifestations of the disease, thinking about secondary prevention paradigm, primary prevention paradigm. So as we think about that from a totality perspective, we think about multiple steps within the treatment of Alzheimer's disease moving forward.

So just to build on that a little bit, we're very early in our work on Alzheimer's. Because up until a few weeks ago, we were primarily focused on rare obviously, orphan monogenic diseases and Alzheimer's is anything but that, at least in general. What we thought about different programs to go after in using gene therapy in this particular case, it's either gene replacement in terms of expression protein or potentially other modalities, such as expressing antibodies or other approaches, we thought about working with -- working on Alzheimer's and thinking about the areas that we've talked about tau and beta amyloid, et cetera, and also potentially other targets, which we haven't really talked about yet. But the idea -- and I think this goes to a little bit of what Gene was talking about is, can you deliver a gene therapy that has a stable and consistent expression of an antibody, for example, that it may have a therapeutic effect that doesn't require compliant -- avoids compliance issues. Obviously, in the context of safe gene therapy. And I understand that, that may be a hurdle, but that's something that we -- that I think feel is really focusing on. That could be a really fascinating approach to have long-term stable outcomes for groups that are either traditionally noncompliant or potentially, to Gene's point, preventative or that have onset likely in the next several years. And that's one approach that we're thinking about in terms of delivering through gene therapy monoclinal antibodies or looking at specific expression of proteins that may have therapeutic benefit as well. So we haven't gone into those targets yet, but -- go back to your question about combination, it is an interesting and fascinating idea of not necessarily requiring multiple drugs being delivered at different intervals and different modalities, either IV or oral to have something like a gene delivery, which is stable and potentially for years on top of other approaches that could synergize. And obviously, those are really long views of where the field could go, but that's certainly something that we're really interested in building on. And I see a lot of complementary approaches that could also have these interventions potentially with either additive or synergistic outcomes.

Absolutely. No, that makes sense. And so actually, before going into some of the other indications, Bruce, I just wanted to actually ask you a follow-up question on -- because you mentioned safety in regards to gene therapies. And of course, FDA held this AdCom last week on that topic, I guess, what, in your view, were some of the key takeaways from that? I know there was obviously some extensive discussion specifically around kind of like toxicity and kind of some of the MRI findings. So I guess if you could kind of help put some of that discussion in context for the viewers, that would be great.

Yes, 2 days in 3 minutes, I'll try. So we came into this thinking that it was looking at all the agenda items and obviously talking to Jim a little bit where he shared that he was going to be on some of the panels. So we just got some ideas of where this would go. And our general takeaway was, I think, how it came out, which was that it was going to information gathering by the FDA, bringing all the known -- generally, the known and severe toxicities together in one place for a discussion about whether that would impact guidelines or potential changes to approaches. And the way we saw this is boiling it down to 3 different buckets. One was systemic toxicities, where generally, the overlay was continue to monitor and be very careful about dosing and thinking about higher doses, especially for liver tox and some of the other outcomes. But systemic tox really is -- it needs very careful animal studies and then careful follow-up. And that theme was generally transferable to the toxicity from a CNS perspective, which came in, again, 2 general areas. One was MRI findings when there were parental injections. And the neurologists essentially said, and the experts basically said, these MRI findings are not unusual. It's not clear whether there's any clinical manifestations and outcomes. And I think that, that also carried forward in DRG toxicity, which obviously Jim has been at the forefront of looking at. Where again, there are a lot of histopathology findings, but not a lot of data on clinical manifestations. We've incorporated, in fact, in our study, based on the work with Jim, sensoring neuro on action potential and nerve conduction velocity into monitoring all of our patients, whether adult or a child. And then looking at potential any sensory neuropathy that might come up later in the studies. So again, intensive monitoring, but not really clear what the clinical outcomes are. And I think the third component, which was not really part of the agenda necessarily, which was on manufacturing. And one of the biggest questions was about empty fill in the capsids. So the capsids can either have a different percentage of empty fill. But there again -- and I think this goes back to gathering data. There isn't a clear indication that a certain ratio of empty fill is either beneficial or harmful. It's more that we know X safety and clinical benefit with X quality control. And so it was more again about, I think, monitoring and controlling that quality, which is again something that we've built an analytics group, and part of that is also going to be looking at empty fill and making sure quality is there. So the overarching outcome was continue to monitor, continue to gather data. There may be some aspects of guidelines for clinical programs that may be looked at by the FDA. But from a Passage Bio perspective, we feel like we're in good shape at the forefront of kind of adopting those. But that's -- and there may be some guidance or there may be some individual clinical studies that are looked at from the FDA to adjust as needed for monitoring. But I think it was a really productive meeting where the data was essentially brought together, I'm not sure that there are any discrete actions coming out of it.

Got it. No, that was super helpful. So now I want to get back to some of the specific indications. So I want to shift to frontotemporal dementia now. And Obviously, Arnon and Bruce are both working on programs in frontotemporal dementia that are geared towards boosting progranulin levels. So I guess maybe if we could talk a little bit about just progranulin in general and kind of your thoughts on the role it plays, not just in patients with progranulin deficiency, FTD, but other forms of FTD, other neurodegenerative diseases. And Gene, you're welcome to comment on this as well. diseases like Alzheimer's, Parkinson's. And then if you could also just talk about your specific approaches as well, that would be great.

Arnon, would you like to go first? Since you're further ahead, for sure.

Okay. Yes. So progranulin is a really exciting target. It's a secreted immune regulatory molecule that has multiple functions. It controls lysosomal function. It controls neuronal survival, it control microglia, the immune cell function in the brain. And it is a very unique target in the way that genetically it was shown to be a risk for practically every nordegenerative disease that's been identified. So loss of like haploinsufficiency in progranulin, like 1 good and 1 bad copy of progranulin invariably lead to frontotemporal dementia with progranulin mutation. But regulatory mutations that decreased progranulin just by 15% to 20% were shown to be risk for Parkinson's disease, for Alzheimer's disease, for a new identify -- newly identified form of dementia called LATE, decreased the level of progranulin also is associated with increased progression rates for ALS, increased progression rate for frontotemporal dementia from other causes as well as earlier age of onset. So it seems that progranulin is sitting like at the top of the neurodegenerative pyramid, most other risk genes are really disease specific, like TREM2 is specific for Alzheimer's disease. Alpha-synuclein is primarily for Parkinson's disease, and progranulin is really unique in this feature. So we are currently in Phase III with a program in elevating drug for frontotemporal dementia with progranulin mutations. We are in Phase II with FTD with C9orf mutations. And we are very close to starting a Phase II in ALS with C9orf mutations. And our approach was to elevate progranulin by blocking the degradation cascade. We've shown that we can triple the level of progranulin by elevating this degradation cascade. And most recently, we presented our Phase II data. We understand the disease cascade. We know that decreasing the level of progranulin leads to lysosomal dysfunction and then to inflammation that part of the readout of inflammation is hyperactive expression of complement cascade. So we show that our drug can normalize lysosomal enzymes and proteins, can normalize complements expression, can reduce the rate of brain tissue rose by volumetric MRI. And based on age match control, we were also able to say that -- show that we can slow down cognitive decline by about 47% to 50%. So this was a Phase II and open-label study. It was a small study. But, again, we are talking about linking biomarkers with clinical data. We see that everything really moves in the same direction, and this really gives us confidence to continue into the -- sort of continue the Phase II in which we are sort of fully recruiting. So because progranulin is such a broad risk genes, we are together with GSK, which sort of is partnering with us on this franchise, we are expanding to Parkinson's disease to Alzheimer's disease. And we are really trying to capture all the indications that progranulin seem to be for. So Bruce...

In 30 seconds, I want to leave a moment for Gene as well. Essentially, we're using an older AAV1, which is shown to have broad genome [Indiscernible] distribution across the brain as well as in the ependymal cells. And we can get to more than 50x the natural level of progranulin and not that we may get there. And we're following a very similar process to Arnon what just alluded to, which is we're just starting the Phase I. And we hope that gene therapy, obviously, can move progranulin to a much higher level. And certainly, the -- we're looking at the indications that are not just described as future possibilities as well. Gene?

Well, I'm going to leave it to the experts. I'll just say, as a neuroscientist, I think it's a very interesting target. I -- obviously, there are some great genetic evidence to suggest progranulin involvement, certainly in FTD. But I think the broader implications are really fascinating, particularly as Arnon, I think you said, the potential applicability across a broad set of neurodegenerative disorders is something that I find quite compelling. So I think it's an interesting target.

I totally agree.

Awesome. Fantastic. Well, I think we're actually out of time. So I don't want to keep you guys too much longer, but it's been fantastic to have all 3 of you together and to kind of go through some of these really kind of pertinent topics right now. So I really appreciate the time, and thank you so much.

Thanks. Neena.

Thanks for having us.

Thank you for hosting us.

Of course.