Bank of America. I'm pleased to be joined by Sara
Kenkare-Mitra.
You got it, right?
President and Head of R&D at Alector. So with that, I'll hand it over to Sara for, for the presentation.
Great.
Yeah. Thank you.
Thank you, everybody. Firstly, it's a pleasure to be here. I'm here again as, Alec said, on behalf of Alector. I'm President and Head of R&D. Firstly, we're going to be making some forward-looking statements today. So here's some disclosures, and also please refer to our SEC filing on our websites. Some of you are probably aware, Alector was founded about a decade ago. We have a bold vision and really a passion to harness the brain's immune system to counteract disease, in the brain. Our innovative science has fueled a proprietary pipeline of novel immunoneurology drugs. We have three clinical candidates in advanced stages of development, and we have data readouts anticipated, from these candidates, with the imminent one being in Q4 of 2024, and that's the AL002 INVOKE-2 phase II data, from early Alzheimer's disease. Additionally, we are well-resourced. We have an experienced team and global partnerships.
Today I'm going to talk about our science, our portfolio, and tell you a little bit about our programs. Our science is an integration of insights from human genetics, immunology, and neuroscience. We know that many gene mutations associated with neurodegenerative disease are immune-related. Excuse me. Microglia are the sole immune cell of the brain. Microglia are critical in the functioning of the brain, the health of the brain. They do a number of different critical activities, including sort of cleaning up the debris in the brain, misfolded proteins, looking after the health of the cells of the brain, ensuring that inflammation is resolved, and overall, they are guardians of the brain. Excuse me. It is this integration of insights between human genetics, immunology, and neuroscience which is the underpinning of the science behind Alector.
You'll see this in every one of our programs, that we are really passionate to utilize these insights into driving our pipeline. As I said earlier, we are well-resourced. We have a pipeline of firsts. We have programs in clinical development. Our progranulin franchise has two monoclonal antibodies, latozinemab and AL101, both in phase I in phase III and I in phase II, and I'll tell you more about these later. Latozinemab for the treatment of frontotemporal dementia in the progranulin mutations carriers, and AL101 in early Alzheimer's disease. This is a partnership with GSK. Our TREM2 molecule is an agonist of TREM2. It's AL002. I'll dive into this a little deeper later. We have a phase II study, INVOKE-2, in Alzheimer's disease. This is in partnership with AbbVie.
Additionally, we have a pipeline of preclinical candidates, and we have our own proprietary blood-brain barrier technology called Alector Brain Carrier, or ABC, that we are utilizing both for novel targets as well as to create second-generation programs. So I'm firstly going to go quickly into the AL002 candidate, particularly because of real interest in this target. We have imminent data coming in Q4 2024. AL002 is a TREM2 activator. Now, TREM2 is a key signaling receptor on the surface of microglia. And essentially, it senses any damage. It looks for stimuli like apoptotic cells, cellular debris, damage to the myelin sheath, misfolded proteins, etc., and regulates microglia survival, proliferation, migration, and function. Additionally, it is also a key genetic risk for AD.
Over 40 TREM2 mutations related to AD have been identified, and it's been shown in GWAS studies that elevated TREM2, which reflects a baseline activation of microglia, is associated with slower cognitive decline in Alzheimer's disease. So with that hypothesis, we engineered a molecule, AL002, which was specifically designed and engineered to bind to the stalk region of the TREM2 receptor, which is again on the surface of microglia. Now, by binding the stalk region of the receptor, it ensures that we are not disrupting the natural ligands that bind to the TREM2 receptor, and it activates signaling of that TREM2 receptor downstream. And this slide merely shows you some of the original preclinical data that you know validated our hypothesis that indeed it binds where it's supposed to bind, and that indeed we get TREM2 signaling.
Now, initially, we started a phase I study with AL002, which was, the molecule had the right pharmacokinetic properties. It was well-tolerated. And we also measured a number of biomarkers to ensure we had target engagement, and that we were getting some evidence and hints of microglial activation. And on this slide, what I share with you is on the left is dose-dependent reduction of, soluble TREM2 in the cerebrospinal fluid, which is associated again, associating this with target engagement. And on the right, you see, dose-dependent elevation of, CSF1R in the cerebrospinal fluid, which again, gives, us evidence of microglial activation. Based on those, successful data in our phase I study, we then designed our phase II study, which is the INVOKE-2 trial, for AL002, again, in participants with early Alzheimer's disease. This is the trial that has the readout at the end of this year.
So I'm going to just talk a little bit about the study. It's a randomized, double-blind, placebo-controlled four-arm study with a common-close design. This study has three dosing arms, three drug arms, with three different doses. The enrollment for this trial was completed in Q3 of 2023, and we expect data from this study again in Q4 of 2024. We do have a long-term extension patients that complete the main study can roll over into the long-term extension. Now, what are we measuring in this study? We have standard clinical and functional outcome measures. A clinical outcome measure is the CDR sum of boxes, again, similar to the primary endpoint of lecanemab in their phase III trials. We have standard secondary clinical functional outcome measures.
What we're doing is we're using a proportional analysis that allows us to use the totality of the data because of the common close design for patients that, you know, are spread across that entirety of the continuum of that study. In addition, this is a very biomarker-rich study. We have biomarkers not only of target engagement but also of microglial signaling and AD pathology. And what you'll see here reflected on the left is really biomarkers of target engagement and microglial signaling. And then on the right, you have your standard biomarkers of disease pathology like imaging biomarkers like amyloid PET, tau PET, as well as plasma and CSF biomarkers measuring plasma phospho-tau, CSF phospho-tau, plasma Aβ 42/40, and a number of other biomarkers. We also have measurements of volumetric MRI in this study.
Now, early on in this study, we did see MRI findings that resemble ARIA. The reason we call it ARIA is because these findings essentially resemble this ARIA that is seen with anti-amyloid therapies in terms of their features on the MRI, the incidence, the timing of onset, the timing of resolution. In addition, what we found was that initially, the predominant symptomatic ARIA was with patients that were homozygous for the ApoE4/E4 alleles. We voluntarily excluded these patients from our study and continued on with the non-ApoE4/E4 population. For most parts, that population, we have seen significant reduction in ARIA, and essentially, clinically serious cases are uncommon. As I mentioned, this is being done in collaboration with AbbVie, and AbbVie has obtained an agreement with us and an option to obtain, based on the data from this study.
I'm going to move on to the progranulin franchise. We have two molecules here, latozinemab, or AL001, and AL101. Both are progranulin elevating candidates. Now, latozinemab and AL101, again, like all our programs, there's a strong biologic rationale and a genetic rationale. So I'll briefly touch upon both of these. Progranulin is known to be a critical immune regulator, a neuronal survival factor, and a lysosomal chaperone. Now, genetics of progranulin are very well defined. These mutations in progranulin are known to be deleterious. In fact, if you look at the heterozygous or 50% loss of mutation, this is where progranulin levels are reduced to 50% of normal. And that is frontotemporal dementia, particularly with patients with the GRN mutation, the subpopulation that we are studying latozinemab in. On the right, you see the mechanism of action of latozinemab and AL101.
Both these molecules bind the sortilin receptor, and the sortilin receptor is a degradation receptor that's responsible for degradation of progranulin. By blocking that receptor, you essentially prevent degradation of progranulin and hence leads to elevation of progranulin. We studied this molecule in a standard phase I SAD/MAD trial and found that AL101 had, you know, good pharmacokinetics, well-tolerated, and moved into and this phase II study in FTD patients. This was an open-label study, and I want to get your attention to the highlighted arm of the study, which was in symptomatic FTD GRN patients. And these were dosed. You see the endpoints on the right. We had clinical outcome measures, target engagement, biomarkers of disease activity, and we looked for clinical benefit in these patients. So firstly, we confirmed that, as expected, progranulin was elevated in plasma and CSF progranulin levels in normal healthy volunteers.
Additionally, GFAP, a biomarker of astrogliosis, so disease activity, was reduced with treatment in these patients, both in plasma and CSF, down to levels that are seen in asymptomatic carriers of that mutation. Now, this was an open-label study. We did look at the clinical endpoint, but we compared it to historical match controls, essentially from the GENFI cohort. That allowed us to really get a sense of the impact of treatment of patients with latozinemab. And we showed we were able to show that there is a slowdown of the annual disease progression. As you compare to these historical match controls, that's about 48%. After that, we started our phase III pivotal study, which is INFRONT-3. And this study, again, is evaluating latozinemab in patients with FTD GRN. We have 103 symptomatic patients and 16 at-risk carriers in this study.
This study completed enrollment in Q4 of 2023. It has a 96-week treatment period. It has all the standard assessments, primary endpoint of CDR plus NACC FTLD sum of boxes, secondary clinical outcomes, and exploratory endpoints that are both imaging as well as soluble biomarkers. Now, AL101, the second program, is being developed to align to the needs of the broader population, like in Alzheimer's disease. Again, underpinnings are genetic and biological. The genetics of progranulin deficiency are strong in in Alzheimer's disease. From a biology perspective, we have shown in disease models that ablation of progranulin exacerbates AD while overexpression is protective in AD. Now, this program completed phase I in healthy volunteers. We now started a phase II study, PROGRESS-AD, which is being operationalized by our partner GSK. The enrollment is ongoing in this study. It was initiated in February of 2024.
This is the design of the PROGRESS-AD study, again, a very standard phase II study, a randomized, double-blind placebo-controlled study, which is looking at efficacy and safety in patients with early Alzheimer's disease. We have two dose levels in this study. The primary secondary endpoints are again very similar to the ones I've shown you with AL002. The biomarkers are imaging and soluble biomarkers. Again, this as I both these programs, these candidates are being developed in partnership with GSK. So with that, I just want to end reminding you that Alector is pioneering immunoneurology. We have a number of firsts. We have three clinical candidates in advanced stages of development and data anticipated in Q4 2024 with AL002, our TREM2 elevating activating candidate. Thank you.