All right. Thanks everyone for being here. I'm Madhu Yennawar. I'm on the biotech team at Leerink, and we have Mike Rosso from Alector here to give us a presentation, so.
Thank you, Madhu, and it's a pleasure to present today here at Leerink. Before we begin, just would mention that, I am gonna make some forward-looking statements today and encourage you to review our statement here and our SEC filings for, for more information. So at Alector, we're pioneering a vision where we're bringing an opportunity to really transform the treatment of neurodegenerative disease based on some fundamental findings on the intersection between immunology, genetics, and neuroscience. And we're gonna talk a little bit about that in the context of a proprietary portfolio of medicines that we're advancing through clinical development alongside significant partnerships, including with AbbVie and GSK, which we'll touch on.
It's an exciting year for the company as we're approaching a major data readout, our first prospective placebo-controlled data readout, and this is on our AL002 TREM2 molecule, and we anticipate data for that program in the fourth quarter of this year. So just a few minutes on the foundation of the company and the science. So you can see here on this slide, on the left-hand side, the human genetics. The fundamental finding here is that you have a number of gene mutations that are associated with neurodegenerative disease that are immune-related, and specifically, mutations that are important in the context of the immune cell of the brain, which is called the microglia. And that's shown schematically in the middle panel of this slide.
The microglia, as the immune cell in the brain, is playing a number of different critical functions for maintaining brain health. As we think about the brain, even though, you know, on a body weight basis, it's not that significant, it's about 20% of our metabolic activity. It's a huge amount of our metabolic activity, and we're constantly creating metabolites and, you know, some of these, you know, can accumulate, become misfolded proteins and cause other pathology. The microglia is playing a critical role in the clearance of these and the maintenance of other activities of brain health.
As we pass through reproductive age, what occurs is the selection pressure on maintaining the activity of this immune cell goes away, and these critical cells can become quiet and less active. What we're seeking to do is basically restore them back to the active and healthy state, and that can be protective in the context of neurodegenerative disease. That's shown on the right-hand side in the context of microglia being critical to kind of nourishing, protecting, and optimizing the function of the brain. So, as mentioned, we're gonna talk today in the context of our proprietary portfolio. On the top, we're showing our two late-stage molecules, which are partnered with GSK. These are progranulin-elevating antibodies.
The most advanced is in a phase III study currently in frontotemporal dementia of patients with a GRN mutation. That's with our latozinemab, latozinemab molecule. Our second progranulin-elevating molecule is AL101, and that's in a phase II study now that's dosing and enrolling patients in Alzheimer's disease. Both of these programs are being developed together with GSK, as I mentioned. Our next program, TREM2, which we'll spend more time on today, is in a phase II study in Alzheimer's disease. This is part of an option deal that we have with AbbVie, and this is progressing towards data, as I mentioned, towards the end of this year.
And then, in addition, we have a proprietary pipeline of novel first-in-class programs that are advancing towards the clinic, and a good number of these are using our brain carrier shuttle technology, which we call ABC, Alector Brain Carrier technology. And this includes a number of disclosed programs in Parkinson's disease and, some undisclosed programs as well. I should mention also, just on this slide, that, we're well-funded. We have $620 million in cash. This provides runway through 2026. That's a full two years beyond our anticipated TREM2 data readout and a full year beyond our anticipated progranulin phase 3 readout, and that doesn't assume any additional milestones from our partnerships.
So, just to spend a little bit of time on TREM2, to go over this program in a bit more detail, and we'll touch on some of the others, just because of the proximity of the data. I think there's a lot of attention right now, and also based on the mechanism of action. So, TREM2, we'll talk a little bit about the biology and how it's differentiated from the other therapies, including the A-beta therapies that are out there.
We'll talk a little bit about the broad mechanism here and why that, that's important, and the potential opportunity, for, clinical efficacy that goes beyond what we're seeing with the current approaches, including the A-beta therapies, and in addition, the potential for, potential, combination, or, or add-on therapy as well. We should highlight that, this program, AL002, is the most advanced TREM2 activating candidate in, clinical development for Alzheimer's disease, and Alector has really pioneered, this work.... So just a few minutes on, the biology here. TREM2 is a key, immune checkpoint on, the surface of the, microglial, cell.
What it is is you can think of it, and this is shown schematically in the little Pac-Man-like structure here on the left: a damage receptor, and it's constantly surveying the brain, you know, for misfolded proteins, other evidence of damage, whether it's, you know, myelin sheath, you know, APOE, you know, amyloid beta, tau. When it sees this damage, it activates a signaling cascade that drives a number of different important activities to maintain brain health. This includes, you know, making sure that the microglia are proliferating appropriately, that they're migrating to the sites of injury, that they're enhancing function, whether it's phagocytosis of misfolded proteins, maintaining oligodendrocyte health, astrocytic health. It's a broad set of activities, and we think that's really key to our approach.
And then shown on the right-hand side here is the genetics. When everything that we're doing is a strong foundation based on the genetics of these diseases. And it's important to note that a homozygous mutation in TREM2 causes dementia in a very severe form. If you have one good copy and one bad copy, you have a substantial increased risk for Alzheimer's disease. And there's a number of different mutations in TREM2 that have been directly related to Alzheimer's disease and additional risks for things like Parkinson's disease and ALS. So the genetic underpinnings here are pretty clear.
Going further, if you have higher levels of TREM2, as indicated by soluble TREM2, a marker of high activity of TREM2, it's been shown that you have a slower cognitive decline in the context of Alzheimer's disease. And this is true both with Aβ and tau pathology, which we think is important. So on the first panel here, you can see higher TREM2 is associated with delayed hippocampal atrophy. In the middle panel, you can see that high TREM2 is associated with slower decline of episodic memory. And on the third panel, you can see that higher TREM2 is associated with slower progression from mild cognitive impairment to Alzheimer's disease. Here, what we show on this slide is that higher levels of TREM2 is also associated with slower accumulation of tau.
As we know, tau is really an important biomarker right now in terms of the overall state of pathology for Alzheimer's. So higher TREM2, slower accumulation of tau. So what we did when we designed AL002 was to find an antibody that's delivered systemically, that can basically activate this signaling cascade, and again, restore this, you know, more senescent microglia to a more active, healthy state. And you can see in the first panel here on the upper left, AL002 binding to the stalk region of this receptor complex. And important, that doesn't line the target sensing region, the area of the receptor that's sensing those folded proteins, but it's basically enhancing the activity of the signaling of TREM2 in the setting of those disease markers.
What we can see is that, shown in the middle panel, when you add AL002 and APOE, you have enhanced binding to APOE. On the right-hand side, you can see in the context of AL002 with phospholipids, you have enhanced binding to phospholipids. On the lower left, you can see that you're activating TREM2 signaling, as indicated by phosphotyrosine kinase activity. We're promoting gene expression with administration of AL002, and again, this is a broad set of activities that the microglia is playing. You're also enhancing cell viability and, importantly, inducing the lysosomal activity. The lysosome in the microglia is a, you know, kind of, you can think of as a trash compactor for these misfolded proteins, and we're enhancing that activity in the site of disease.
Here, we're showing, importantly, the potential, and how this may be used with anti-Aβ therapies. So if you have TREM2 deficiency, it reduces the efficacy of, amyloid clearance by the Aβ therapies. This, this has been shown. So, you know, we see a significant opportunity for the potential, expansion of what you see with the Aβ therapies with, with TREM2 activation, and potential combination. So we've moved through a phase I study in healthy volunteers, successfully completed multiple, doses, no significant safety issues, well tolerated in, in healthy patients, healthy volunteers. And then, in addition, we showed in, in these, healthy volunteer studies, strong evidence of target engagement as shown by, reduction in soluble TREM2. This is in, in the, case of AL002, an indicator of target engagement.
And then on the right-hand side here, a strong, dose-dependent elevation in, CSF1R, which is an indication of microglial activity. Based on this activity, we advanced, AL002 into a phase II study, which we're, wrapping up this year. This is a, three-dose arm, and also placebo. So four total, arm study, common close, randomized, prospective, double blind, phase II. And so common close, just a minute on this because, it's, a, a bit different than if you had a specific, endpoint. So basically, what you're doing is timing the overall study based on when the last patient enrolled completes 48 weeks of therapy, and you're gathering the, data on all of the patients that have been treated, prior to that for up to 96 weeks.
So you have a broader set of data upon which you're performing your statistical analysis. So we're looking at patients. 381 patients have been randomized, and we'll be looking across this time period from 48-96 weeks. And then, after patients complete 96 weeks of therapy, they have an opportunity to go on to the long-term extension study, which is also blinded to the original treatment assignment, and it gives us additional data on the treatment over a longer period of time. So again, we anticipate data from the treatment portion of this study by Q4 this year. And then, in addition, we've had very strong enrollment into the long-term extension study.
Over 90% of the eligible patients from the treatment period have gone on to the extension study that have been eligible at this point so far, which is encouraging. What we're looking at here, so the primary outcome measure is Clinical Dementia Rating Scale, so CDR sum of boxes. This is what's been used with the anti-A- beta therapies, lecanemab and donanemab and others, as the primary endpoint of the phase III studies. We're also looking at secondary clinical and functional outcome measures, and, you know, these are listed here. So RBANS, ADAS-Cog, MMSE, and we're using a proportional analysis for this phase II. So again, using all of the data that we collect in the common closed design trial.
Importantly, in addition to the clinical and functional endpoints, we're measuring indicators of target engagement and microglial signaling. So this includes measuring, you know, soluble TREM2 in the CSF and in the plasma. We're also measuring other markers of microglial activity, including CSF1R and other measures. And importantly, we're measuring a number of different biomarkers around Alzheimer's disease pathophysiology. So this includes amyloid PET, tau PET, plasma phospho-tau, CSF and plasma phospho-tau, based on other more novel biomarkers, including the microtubule binding region measures, and in addition, CSF and plasma Aβ. And that's really important from our standpoint to be looking at kind of the broader indicators of disease progression beyond just the clinical reads. We'll also have measures of other broader activities of microglia.
This includes measures of astrogliosis, as measured by plasma GFAP, CSF YKL-40, and other indicators of neuronal and synaptic injury, including NfL, and other measures, including imaging and volumetric MRI. So overall, this is meant to be a pretty broad picture of what's happening in the setting of Alzheimer's disease with TREM2 activating treatment. One point to call out is that we have been seeing in the phase II indicators of what appears to be ARIA. And ARIA is an MRI finding, amyloid-related imaging abnormality, which in most patients is the vast majority of patients is completely asymptomatic and is solely an imaging finding.
But whether it's with lecanemab, donanemab, some of the A, A- beta therapies, this has been seen, and in some patients, it is a, it is symptomatic, and it's something that we have to focus on, importantly, from a safety perspective. And what's interesting here is, while the overall rates are similar to what's been seen with the A- beta therapies, and, you know, we're only a significant minority have been symptomatic with just a couple patients that are clinically serious among the study population. And even in these patients with, you know, removal of drug, they, you know, recover and do well.
So this is a manageable issue, but it suggests that there's something going on biologically with this molecule, and you know, it's something that we're watching closely. And the fact that you're seeing ARIA with the anti-A- beta therapies, which are, you know, focused on amyloid beta removal, and you also see what appears to be ARIA in the context of TREM2 administration, you know, suggests biologically that whether it's removal of A beta or you know another approach, there's some kind of biological activity here that could be important. So what are we looking for in the AL002 study? What are our goals for the study both the main study and also the long-term extension?
We'd like to see therapeutic restoration of microglial function, and we'd like to see this, you know, slowing Alzheimer's disease progression. Ideally, you know, what we're gonna see is that, we're enhancing the clearance of misfolded proteins, including amyloid. We're anticipating that we can see other beneficial effects on microglial and, brain health, including, ideally, the maintenance of synaptic connections, supportive astrocyte and oligodendrocyte function, maintenance and repair of the blood-brain barrier and vasculature, and preservation of immune tolerance. So we're looking to see a broad, potential set of, of benefits.... Ideally, we're gonna see a slowing of disease progression in this study, and, to see that supported by a combination of, other clinical, functional, and, biomarker readouts.
Given the multiple mechanisms by which microglia protect the brain against neurodegenerative disease, we see this as an opportunity to have a broader potential benefit than we're seeing with the current, more focused A-beta driven therapies. So, you know, from our standpoint, we'd like to see, you know, an indicator of biomarker response. And, you know, as we know, the A-beta therapies, you know, can reduce the amyloid beta plaque level, you know, very significantly. What we'd like to see is a broader potential indicator of benefit beyond just removal of A-beta plaque. And, again, you know, because the broader mechanism of action, you know, we see that there's a broader potential benefit, but there's also potentially a temporal benefit as well.
So, you know, there's an opportunity with this approach that you may see that microglial improvement in microglial function could help patients across the disease spectrum, whether on the early side or maybe even on the later side. So that's something we'll be looking at carefully. So, just to note, as I mentioned earlier, this program is part of an option deal with AbbVie. They've paid us nearly $250 million upfront already, both in the context of their upfront payments, equity investment, and additional milestone payments that they've supported us with to this point. In addition, post completion of this phase II, we'll be delivering a proof of concept package to them.
Based on delivering that package, which, we anticipate, you know, we can deliver by the end of this year, they'll have 90 days to determine if they'd choose to opt in. If they do, that would be a $250 million payment to Alector. And at that point, we would share, 50/50 in, additional, development and also, profits, down the road. And the $250 million payment largely covers our, our portion of the additional development spend that's anticipated. So it's an exciting deal for us. So with that, I know we only have a, a little bit of time, remaining, but I wanna briefly touch on latozinemab and our proprietary pipeline, and then I'll, I'll just wrap it with some, some outlook, and happy to take some questions.
So latozinemab and AL101 are our progranulin elevating programs. These are being developed in both frontotemporal dementia and Alzheimer's disease, and these are the most advanced progranulin elevating programs in development currently that we're aware of. So, just a word on the genetics here. So again, you know, strong underpinning. You know, there's a clear indicator that if you have mutations in the progranulin gene, you're at severe risk for significant neurodegenerative diseases, including frontotemporal dementia. And then, if you have other genetic changes, you can have significant increased risk, including for Alzheimer's disease, ALS, Parkinson's disease, and other forms of frontotemporal dementia. This is a broad potential opportunity with elevating progranulin. So, frontotemporal dementia, this is a very severe form of dementia.
There's no approved treatments currently. It's a rapidly progressing devastating disease. Some folks know, for example, some notable folks, including Bruce Willis, Wendy Williams, both were recently you know public about the fact that they have frontotemporal dementia. It's often misdiagnosed. It can be misdiagnosed and confused with Alzheimer's disease, depression, other settings and it's a significant unmet need. So the way our programs work, latozinemab and AL101, is by inhibiting a degradation pathway for progranulin called sortilin. And by inhibiting this pathway, you're basically elevating the progranulin levels in the case of frontotemporal dementia patients with a GRN mutation, you're restoring it back to normal.
So, again, I'm moving through this portion quickly just for time, but we're now in possession of data from a phase 2 study in frontotemporal dementia. This was a matched historical control study, where we showed some interesting evidence of activity, both from the standpoint of clinical and also a biomarker activity. We measured a multiple set of markers, including plasma and CSF progranulin, different measures of lysosomal function, inflammation, brain health, brain atrophy, and also clinical assessments. We showed that we could restore progranulin back to normal levels, both in the plasma and CSF. We showed that we had improvement in disease markers of activity, including GFAP, a measure of astrogliosis.
We showed multiple different normalizations of lysosomal and inflammatory biomarkers, and also evidence of improvement from a brain volume perspective, including biometric MRI measurements of brain atrophy. On a clinical basis, as compared to a matched historical control database, we showed approximately a 50% reduction in disease progression over a treatment period of 12 months. This has now been moved into a phase 3, and we're advancing this. We've completed enrollment in the phase 3, ahead of our target of 90-100 symptomatic patients, with 103 symptomatic patients and patients with FTD-GRN... and we're looking forward to the data from this study, approximately, it's a 96-week treatment period.
We completed enrollment end of last year, so it'd probably put data towards the end of 2025, early 2026. AL101 is our second molecule that's being developed for progranulin elevation. This is in the setting of Alzheimer's disease. Progranulin ablation exacerbates Alzheimer's disease in disease models, and progranulin overexpression is protective in Alzheimer's disease. So we're excited about the opportunity in Alzheimer's disease with our AL101 progranulin-elevating molecule. And this has been moved into a phase II study called our PROGRESS-AD study, where we recently just dosed our first patient. So just to note, this program—these programs are partnered with GSK as part of a significant deal with $700 million up front, and there's $1.5 billion in potential milestone payments.
It's a 50/50 U.S. profit share deal with tiered double-digit royalties outside the U.S. Significant milestones, including $160 million for the first commercial sale in the U.S., $90 million for first commercial sale in EU countries. And just in the last couple minutes, I'll mention that we have significant proprietary drug discovery activity, including a proprietary iterative machine learning-based model for developing novel programs. And in addition, we have advanced our own proprietary Alector Brain Carrier technology. So, this is technology that is applied to our antibodies and other targets of interest to bring higher concentrations into the brain, and we can do this in a versatile format. And, we're advancing a number of disclosed and undisclosed programs using this technology.
Shown here is just an indicator that we can have a tenfold increase in brain uptake using our technology. So, just to wrap it up, it's an exciting time for the company, as we've completed enrollment on our AL002 program and are progressing to data on that in the TREM2 activating setting for Alzheimer's disease end of this year. We've completed enrollment for our AL101 lecanemab AL001 lecanemab program and are progressing to data on that pivotal phase 3 in FTD-GRN by, like I said, ideally end of 2025, early 2026.
We also recently received breakthrough designation on that program from the FDA, which is, I think, a nice endorsement of the data to date, and we're advancing our AL101 program in Alzheimer's disease in phase II, as well as our proprietary pipeline, including our Alector Brain Carrier technology programs. And we appreciate the opportunity to present.
Great. Thank you so much. Actually, I think we're about out of time, so, but really appreciate the update.
Thanks, Madhu.