Good morning, everyone. Thanks to Mark and the Leerink team for having us today. I'm Marc Grasso. I'm the Chief Financial Officer at Alector, and I look forward to providing an overview for the group today. Just a comment: I will be making some forward-looking statements and encourage you to review our SEC filings for more information. At Alector, we have a bold vision, one in which we seek to make degenerative brain disorders history. There has been progress in the field recently, which is encouraging, including around the Aβ therapeutics, but we see that there is much more opportunity to go.
As shown on this slide, you'll see on the left our core scientific approach, which is a three-R strategy where we're removing unwanted proteins, replacing proteins that may be missing or enzymes that may be missing, and restoring activity in the brain, healthy activity in the brain. We have novel programs that are late-stage in development, including a fully enrolled pivotal phase three in frontotemporal dementia, which has received breakthrough designation by the FDA, which will be reading out in the fourth quarter of this year. We're also approaching complete enrollment in our phase two study for our second progranulin-elevating program in Alzheimer's disease. Both of these programs are partnered with GSK, and I'll touch on those in more detail. In addition, we'll also touch on our proprietary technology, which is a versatile brain shuttle technology, which enhances the delivery of novel therapeutics to the brain.
We're a well-resourced company with over $400 million in cash. We have strong leadership and significant resources, and we're in a strong place relative to our partnering strategy as well. This slide is just a snapshot of our current portfolio. At the top, you see the two progranulin programs, latozinemab, which is in, as I mentioned, a phase three study. This is in the setting of frontotemporal dementia for patients with a GRN mutation. I'll touch on that in the data supporting that program today. Our second progranulin-elevating program, AL101, which also is an antibody, is in the setting of Alzheimer's disease. At the bottom, we'll also spend some time today on our proprietary wholly-owned portfolio of Alector Brain Carrier programs and novel programs which are advancing towards the clinic and are addressing significant unmet need in the fields of neurodegenerative disease.
We have over $400 million in cash, as mentioned, at the end of the year, and this is runway through 2026. Let me turn now to our progranulin programs. First, I'll start with frontotemporal dementia. This is a rapidly progressive form of dementia. It's the most common form of dementia for patients under the age of 60, and it's often misdiagnosed. It can be misdiagnosed with depression, Alzheimer's disease, Parkinson's disease, and other psychiatric conditions. It's a very devastating disease. It has compulsive behavior. You can have apathy, anxiety, aphasia. This is the form of dementia, for example, that Bruce Willis recently came public with. There's no approved treatments to cure or slow the progression of frontotemporal dementia, and this is an area that we've helped pioneer in the field. What is our approach? On the right-hand side, you can see how latozinemab works.
What it's doing is binding a degradation pathway for progranulin, which is called sortilin. Our antibody, as shown on the cartoon on the right, is binding the sortilin receptor, and that's elevating progranulin. Why is elevating progranulin important? In the setting of frontotemporal dementia, there's a genetic underpinning for this disease, as shown on the left. If you have two bad copies of the progranulin gene, you die at a very young age of a severe disease, a severe form of dementia and neuronal ceroid lipofuscinosis. If you have one good copy and one bad copy of progranulin or a heterozygous mutation, you have half the normal levels of progranulin, and you will have frontotemporal dementia with onset by about 60 years of age with a 90% penetrance. This is the setting that we're pursuing initially in our late-stage development.
If you have other mutations, non-coding mutations, approximately 10%-20% loss of function, you increase your risk significantly for a number of degenerative brain disorders, including ALS, Alzheimer's disease, Parkinson's disease, as well as frontotemporal dementia. We see this as a key area for development. Note that progranulin is a critical factor in healthy brain function as we get to later life, and it's known to be a highly conserved protein throughout evolution. It's a critical immune regulator, a neuronal survival factor, and a lysosomal chaperone. By replacing this in the context of frontotemporal dementia with a GRN mutation or elevating this in the setting of Alzheimer's disease, we see this as a breakthrough potential approach for frontotemporal dementia and other degenerative brain disorders. Shown here is just a schematic of the phase two that we have completed in frontotemporal dementia.
You can see that we enrolled asymptomatic patients with frontotemporal dementia with a GRN mutation, symptomatic patients for patients with a GRN mutation, and then also some patients that had a C9ORF72 mutation, also with frontotemporal dementia. I am going to spend time today mainly in the middle section, which is the population, which is also the setting for our pivotal phase three. We looked at safety, tolerability, PK/PD, and also a number of additional endpoints, including different biomarkers, brain imaging, and clinical assessments, and I will share that data with you today. Turning to the key biomarker, which is the elevation or restoration of progranulin to normal levels, what is shown here is a comparison prior to treatment and then post-treatment as compared to levels seen in age-matched controls for healthies.
You can see that pretty consistently, both in the plasma and in the CSF, with administration of latozinemab, you're restoring the progranulin levels basically back to normal, which is a key finding for our approach. If you look at other markers of disease activity, this is a measure of glial fibrillary acidic protein, which is an important marker of astrogliosis or inflammation in the brain. You compare this to asymptomatic carriers of the GRN mutation population, you can see that, again, you're restoring this disease marker back to the normal range, another key finding. We also looked at the progression of disease from a clinical and functional standpoint. This is basically an adapted CDR plus NACC FTLD sum of boxes for frontotemporal dementia. Patients with frontotemporal dementia have speech and behavioral facets.
Similar to the Alzheimer's disease CDR sum of the boxes, we have an adapted CDR plus NACC FTDLD sum of the boxes for frontotemporal dementia. This is a well-studied approach in this setting. We compare our disease progression in the phase two to age-matched historical controls in the longitudinal databases available, which the investigators studied closely. This is a comparison that shows approximately a slowing of disease progression by nearly 50% over a 12-month period. This is what we're seeking to confirm in our phase three prospective placebo-controlled study, which I'll turn to next. Here is the design of our phase three. This is a 96-week study. It's placebo-controlled. It's in 103 symptomatic patients and 16 at-risk or asymptomatic FTD GRN carriers.
What we're looking for as the primary endpoint is the slowing of disease progression as measured by the CDR plus NACC FTLD sum of boxes. The sum of boxes approach is adapted to FTD. We're also looking at key secondary clinical outcomes, and there's a number of different measures here for cognitive and functional benefit. There's a significant range of biomarkers we're looking at as well, including volumetric MRI and other biomarkers. This is placebo-controlled, prospective, and it's fully enrolled at this point, and data will be in Q4 of this year. In addition, we're also advancing a second progranulin-elevating antibody, which is AL101. This is in the setting of Alzheimer's disease.
As you can see here, this is the schematic for the study, and we're looking at two different doses, a higher dose and a lower dose as compared to placebo in a phase two. This is a randomized prospective study. We're looking at the primary endpoint as change in baseline from the standpoint of CDR sum of the boxes. We're looking at this at 52, 64, and 76 weeks. We're also looking at key secondary endpoints, including a number of different cognitive and functional endpoints and a range of biomarkers, including amyloid PET, tau PET, CSF, and plasma. This study has enrolled quite well. We're ahead of our target. We're guiding that we'll complete enrollment by mid this year, and I think we're nearly there. Just to touch on our partnership with GSK, we have a significant partnership with GSK on both of our progranulin-elevating antibodies.
This was a $700 million upfront deal with a billion and a half in development and commercial milestones. It's a 50/50 profit share in the US, and we share commercialization with GSK. We take the lead in the orphan indications, including FTD GRN. Outside the US, it's tiered double-digit royalties that are economically approximate to the 50/50 in the US. Very significant downstream economics. There's also significant milestones. There's a $160 million milestone payable to us for the first commercial sale in the United States. There's a $90 million milestone for the first commercial sale in the EU. As noted earlier, this is an exciting program that's advancing towards phase three data in Q4 this year for latozinemab and phase two enrollment completion by mid this year with data we anticipate in the 2026 timeframe.
I should note that latozinemab also received breakthrough designation from the FDA in the setting of FTD GRN. A lot to be excited for on the progranulin front. Shifting gears with the remaining time, I'd like to touch on our Alector Brain Carrier technology in our earlier proprietary portfolio. What is Alector Brain Carrier? This is enhanced brain delivery for novel and best-in-class therapeutics. What we're seeking to do is widen the therapeutic window for these critically important brain therapeutics. Why is this important? We want to lower the cost of goods. When you're giving systemic naked antibodies that have relatively poor penetrance into the brain, you have to do it often at very high doses, and that can be expensive. It's also potentially inconvenient.
If you're having to go in for, as currently is the case for the Aβ therapies, either once monthly or twice monthly infusions in infusion centers, that's much less convenient than if you can have an at-home subcutaneous delivery. This approach potentially allows much more appropriate cost of goods and better convenience. In addition, there's really critical pieces in terms of how we're optimizing the therapeutic window for these novel therapeutics. There's versatility. We can apply this to antibodies, to proteins, to enzymes, and nucleic acids. That widens the opportunity from the standpoint of therapeutic approaches significantly. There's also tunability. What does this mean? This means affinity for pairing to the shuttle technology. This is really critical when you're trying to tailor and minimize side effects and maximize the therapeutic potential. We'll touch on that in more detail.
There is also translatability, which is really speaking to how rapidly we can progress these programs to patients and to eventually the market. Shown on the right-hand side is the most well-known example, which is using the transferrin receptor on the surface of reticulocytes, basically to allow internalization, transcytosis, and exocytosis across the blood-brain barrier. This is an approach that we are using along with our proprietary therapeutics in an optimized way. That is shown on the top here, the iron transport approach. This has potential for neurons, for microglia across the brain. It has high expression level on the blood-brain barrier, and we can get the drugs where we want them in high penetrance. Shown below is a second approach that we are also evaluating, which is an amino acid transporter called CD98 heavy chain.
This also has significant potential for therapeutic cargoes delivered locally in the brain. This shows schematically the difference between using the brain shuttle and just a naked antibody. On the first panel, you see relatively significant penetration only on the periphery. If you look on the right-hand side, you see very significant penetration across the entire brain section. This is, again, an opportunity to use a much lower dose and have much higher penetrance and a better therapeutic window. Let me now take this technology and apply it more specifically to our programs. The first one I'd like to talk about is a brain-penetrant anti-Aβ antibody. This, we believe, has best-in-class potential.
For those following the field, they'll know that Roche has made some progress with what was a naked antibody called gantenerumab, which had mixed results in the clinic and high incidence of side effects, including ARIA, which is a pretty significant concern for the Aβ therapeutics. They applied a transferrin receptor brain shuttle to this, and they've been able to show that they're able to reduce the ARIA quite significantly, enhance brain penetrance while they are still managing some concerns around the side effect and with anemia. What we're doing is seeking to take the best of what's been developed in the anti-Aβ space and optimize it with our own proprietary approach. The first thing we've done is we've optimized the engineered binding to the plaque epitope. We're using the anti-PyroGlu-3 epitope. This has been shown to have the best-in-class plaque removal.
We've also optimized in the second piece the constant region for the antibody. This is really critical, we believe, to optimizing the immune system's removal of the plaque. You're basically using the antibody to bind the plaque, but then the constant region is recruiting in the brain's immune system to clear the plaque. We've optimized that piece. The third piece is optimizing the brain shuttle. That is a combination of the binding epitope and the affinity to the brain shuttle and optimizing the linker. We've done this in a way that we believe is going to have best-in-class potential in terms of minimizing the side effects and maximizing the therapeutic window. This is scheduled to be in the clinic next year. We're excited about the progress on this program. The next program I'd like to touch on is our brain-penetrant GCase replacement therapy.
Those following the field know that there have been GCase enzymes developed peripherally for the treatment of Gaucher disease. There is also central involvement, not only in Gaucher disease, but associated with significant aspects of Parkinson's disease and Lewy body dementia. Having a brain-penetrant GCase replacement could have significant potential. The naturally occurring GCase enzyme is unstable. It is short-lived. It is difficult to manufacture, and it is unable to cross the blood-brain barrier. What we have done is engineer an active, stable, developable, minimally immunogenic GCase enzyme, which is proprietary to Alector, which is compatible with a brain shuttle format. We are able to demonstrate that we can increase GCase levels and have significant potential benefit in these neurodegenerative diseases of significant unmet need. Our approach is shown on the right. We have an engineered enzyme and a linker to the rest of the antibody construct.
We've optimized a transferrin epitope, and we've optimized, again, the affinity. We have a constant region, which is designed to be optimal. This is a case where you're not trying to have immune activation, and you're not trying to have an immune system that's coming in and enhancing any activity. What you're really trying to do is just get this enzyme across the blood-brain barrier and into the brain in the areas where it can have its enzymatic activity, which is going to be helpful and beneficial. Again, this is wholly owned, proprietary to Alector, and is advancing to the clinic next year. Just touching on a few other exciting programs that we're advancing. We are also advancing a novel Reelin modulator. This is something that is replicating the protective effects of a gene mutation, which is very interesting in the field of Alzheimer's disease.
As folks may know, Alzheimer's disease has pathology both from the standpoint of amyloid deposition in the brain, but also tau deposition in the brain. There is a mutation, a presenilin mutation, which has been shown to basically decouple the amyloid pathology and the tau pathology. There is a population that is basically significantly protected from the development of the pathological consequences of Alzheimer's disease. We are seeking to basically replicate this protective genetic finding in the context of a novel therapeutic approach. More on this to come. At this point, we believe we are the only company that we are aware of that is developing a Reelin modulator. Lastly, I want to touch on our two tau programs. We are developing a tau antibody that has potential best-in-class and also a tau siRNA. These are both using our Alector Brain Carrier technology.
The most promising current anti-tau antibodies target the tau microtubule binding region and show early potential promising results in human trials. These are naked antibody approaches, and we're seeking to optimize the therapeutic window and maximize the therapeutic benefit by attaching a brain shuttle. More to come on the antibody approach. An siRNA approach has the potential to directly address tau and prevent the synthesis of tau mRNA and protein. This has the potential for peripheral delivery with our brain shuttle and also potentially have significant change in disease progression. Excited very much about the progress with the proprietary pipeline and more to come on all these programs in the near term. With that, I'll just summarize our accomplishments to date. In the first panel, we're pioneering first for patients.
Our current phase three for latozinemab and FTD-GRN, as noted, is fully enrolled, and we anticipate data in Q4 of this year. Our phase two for AL101 is nearing completion of enrollment and will have data in 2026. We are excited about the progress we are making on our proprietary pipeline of first-in-class and best-in-class approaches for a range of unmet needs in the brain. Our goals for the next three years are shown in the middle panel. We are seeking to deliver our data from the pivotal phase three, the phase two for our second program, as well as providing critical data around our blood-brain barrier technology and our wholly owned portfolio of novel and best-in-class therapeutics. Beyond that, we are looking to obtain regulatory approval and commercialize latozinemab and FTD-GRN in the coming years.
We are also looking forward to sharing additional clinical data for our proprietary programs over this timeframe and advance the science in these areas of significant unmet need. As noted, we are doing this from a relatively strong cash position, $413.4 million in cash at the end of the year as runway through 2026. That does not assume any of the milestones from GSK. It does not assume any partnering of any of our proprietary programs. We have had a strong record of partnering in the past. Thank you very much for your attention today, and happy to take any follow-up.