Hi, good afternoon, everyone. It's 12 o'clock, so good afternoon, everyone. I'm Andrew Fine. I'm one of the biotechnology analysts at HC Wainwright. It's my pleasure to introduce the next company speaking today, which is Alector. Here from the company is its Chief Financial Officer, Marc Grasso. Thank you.
Thanks for having us, Andrew. Great to be here.
Maybe the best place to start is just, you know, not sure how familiar everyone in the room might be. Just kind of getting everyone up to speed, and then we'll dive into specific questions from there, maybe.
Yeah, happy to do it. Elector is a company that's pioneering disease-modifying treatments for unmet needs in neurodegenerative disease. The company is at an advanced stage from a development perspective. We have a fully enrolled phase III study that's reading out in Q4 of this year in a very unmet need in the setting of frontotemporal dementia. These are patients that have a GRN mutation, patients that have half the normal levels of an important protein called progranulin. With our antibody therapy, we're restoring the levels back to normal. This is a program that is partnered with GSK in a large partnership that had a $700 million upfront associated with it. There's a billion and a half in development and commercial milestones.
We also have a second progranulin-elevating antibody that's part of this partnership that's in a fully enrolled phase II study in early Alzheimer's disease. The progranulin biology is a very important biology in evolution. Again, we're restoring levels back to normal in the FTD GRN population. In the Alzheimer's setting, we're elevating progranulin levels in an effort to slow or reduce the disease. We also have a number of Alector Brain Carrier programs. This is using our proprietary brain penetrant technology, including a program around Aβ and a program around the GCase enzyme.
The Aβ program, for those that are following the field, this is an exciting development in Alzheimer's disease, where we've seen for the first time slowing of disease progression with Aβ therapeutics, although the naked antibodies do have some challenges, both from a side effect perspective as well as just from an uptake perspective, from a patient perspective. We are seeking to improve on those by having potential best-in-class plaque removal, but with a brain shuttle also allowing lower dosing, potential subcutaneous dosing, and improving the side effect profile, and potentially significantly reducing RA, having a better side effect profile, perhaps relative to anemia, and improving the overall disease-modifying potential.
The GCase program, which we're pursuing, and this is a subset of Parkinson's disease that have GBA mutations, and also we're interested in Gaucher's disease as well as an engineered enzyme that is, again, brain penetrant using our Alector Brain Carrier technology. The current approaches for Gaucher's, you know, you can administer the enzyme peripherally, but you're not getting good brain uptake. And many of these patients have neurologic involvement. And the GBA mutant patients in Parkinson's disease represent a significant percentage of Parkinson's. And again, having a brain penetrant enzyme could be a substantial change to the care paradigm.
Great. Maybe just going back to the FTD program, maybe you can, you know, kind of set the stage for people in terms of expectations, you know, importance of progranulin biology and, you know, how they should be thinking about interpreting the results when they come out.
Yeah, absolutely. Maybe first, just, you know, setting the stage in terms of how this antibody works and some of the phase II data, and then maybe a bit on the phase III. The way our antibody works to elevate progranulin is by blocking a degradation pathway and inhibiting something called sortilin, which is a cell surface receptor that is one of the pathways for degrading progranulin, regulating progranulin. By our antibody binding sortilin, we're able to show, and we've shown this in the phase II in patients, as well as earlier studies, that we can restore the progranulin levels back to normal. Also in the phase II, in addition to showing restoration of progranulin levels, we see encouraging changes on other biomarkers. We show a reduction of glial fibrillary acidic protein back to levels seen in, you know, presymptomatic patients.
We've seen improvements in volumetric MRI as measuring brain atrophy or ventricular size. We've seen also other biomarkers, including, you know, stabilization of NFL. And we showed approximately 50% slowing of disease progression as measured by a clinical endpoint, CDR plus NACC FTLD, some of the boxes, which is basically an adapted CDR, some of the boxes in the setting of frontotemporal dementia with two domains, behavior and speech. That slowing of approximately 50% of disease progression is really a significant finding in our view from a clinical standpoint and is something we're seeking to show as well in the phase III. The phase III is a much larger study than the phase II. The phase II, we had 12 symptomatic patients with FTD GRN. In the phase III, we've enrolled 103 symptomatic patients with FTD GRN.
We also have 16 at-risk patients as well that are part of that study. This is a 96-week treatment, so it's twice as long as the phase II. It's a study that's measuring the same endpoint, the CDR plus NACC FTLD some of the boxes as the primary. We also have a number of very important secondary endpoints, clinical functional endpoints, as well as biomarker measurements, including progranulin, GFAP as mentioned, NFL, volumetric MRI. This study, as mentioned, will read out in Q4 of this year. I should also note that the FDA has granted breakthrough designation around this program, and that was based on their review of the phase II data and data we have to date. We view this as a very robust study from the standpoint of evaluating this approach to therapy in this significant unmet need.
You know, it should be the basis for, if we're successful with this study, engaging with the FDA around approval.
Maybe in the context of the FDA, maybe we can speak further to the implications for their feedback to you previously, that biomarkers would be accepted and considered in the interpretation of the data and why that's important and kind of your ongoing dialogue with the agency ahead of the results.
Yeah, yeah. We have had an ongoing dialogue, you know, together with our partner, GSK, and the FDA. It has been constructive, as mentioned, the breakthrough designation has helped. You know, we have taken advantage of that in terms of more regular interactions with the FDA. In mid of last year, we had an engagement with the FDA where we were able to confirm, you know, their, you know, support that the biomarkers, particularly, you know, progranulin and other measures, could be supportive evidence in the context of potential filings. We view that as encouraging. You know, our base plan is to file for complete approval with the overall data set. Again, that is using the primary endpoint of CDR plus NACC FTLD, some of the boxes within the symptomatic patient population.
We, you know, reached agreement with the FDA that primary analysis would be on the symptomatic population. We're well-powered for that endpoint with 103 symptomatic patients. If we're able to see, you know, a slowing of disease progression of between, you know, 25-40%, I think we're well-powered for that being statistically significant. If for whatever reason, you know, we don't see, you know, statistical significance on the primary endpoint, we also think there's a potential strategy with the totality of the data to go back, including around some of the biomarkers. There is no approved therapy for this disease, no disease-modifying therapies available. It is a significant unmet need. You know, we think there's potential for different avenues to go back.
Okay, that's helpful. Maybe, you know, it comes up so much, I guess, since you're in the throes of dialogue with the agency on an ongoing basis. Has anything changed? I mean, has the kind of consistency and level of interaction remained constant, you know, or people? What's your take on this?
Yeah, I think just given the current environments, that's an understandable question. It's important to note that we're on the CDER side, not the CBER side. There hasn't been any significant change that we've seen at this point, which is encouraging. Again, given the unmet need, you know, given, you know, the potential for disease-modifying therapy in this, you know, severe setting, you know, we think we're, along with the breakthrough designation, you know, in a reasonable place with this robust study. There hasn't been anything that we've seen so far that would suggest that there would be a delay or a change in the review process.
That's very helpful. Maybe we can speak more about the progranulin program now. You know, the company's done a lot of work, but, you know, speak about, you know, why it's an important target for AD and the implications.
Yeah. As mentioned, in the setting of FTD GRN, you have half the normal levels of progranulin if you have one good copy and one bad copy of the gene. That is the primary for the phase III latozinemab program. We also have a second progranulin-elevating antibody, AL101. This is in a phase II study that is fully enrolled for early Alzheimer's disease. What is known in genetic data is that if you have partial loss of function of progranulin, you are at higher risk for developing Alzheimer's disease. In addition, it is shown that if you are able to elevate progranulin in animal models, it can protect against Alzheimer's disease or reduce the severity of Alzheimer's disease. That is the basis of the effort for AL101. The phase II study is now fully enrolled. It is a 76-week study at two different dose levels versus placebo.
It's a primary endpoint of CDR, some of the boxes, which is, you know, the standard in this area. There's also a robust set of additional clinical and functional measures and other biomarkers, including amyloid PET and other outcome measures. You know, from the standpoint of determining if progranulin elevation can have a benefit in Alzheimer's disease, we think this is a robust study. That's fully enrolled in April of this year. It's a 76-week treatment period. You know, we're hoping that we can have data, you know, towards the end of 2026 for this program.
How is the progranulin program, the study, different from the TREM2 trials?
Yeah, yeah. TREM2 biology is a very different biology. We, with progranulin, are again increasing the levels of a protein that can be potentially protective in the context of neurodegenerative disease. TREM2 biology is more the activity of the microglia in the context of pathology such as Alzheimer's disease. Very different biology between the two. And, you know, for progranulin, again, we're basing this on the strong genetic evidence as well as the available earlier animal data in this context.
Were there lessons, I guess, learned from the TREM2 trial experience in terms of patient selection or endpoint selection that are now influencing the progranulin program?
Yeah, I think from TREM2, you know, there's a lot still to be understood as it relates to the biology and how best to impact disease. You know, we continue to review the data and assess. At the moment, it's not a priority from a development perspective for us. As it relates to the, you know, the phase II in early Alzheimer's disease, in some respects, it's a similar patient population. It's a similar set of endpoints in terms of the phase II that we also pursued for TREM2. We think that was a very well-run study, and it answered the question. It's not a substantially different patient study from a design perspective or endpoint perspective.
Maybe you can speak about the ABC platform and, you know, kind of differentiate it in the context of the landscape.
Yeah, yeah. We're very excited about Alector Brain Carrier, which is our proprietary brain penetrant technology. We're applying this to a number of different programs. It's applicable to antibodies such as our Aβ program. It's also applicable to other proteins and enzymes, including our GCase engineered program, enzyme replacement program. It can also be applied to nucleic acids, such as siRNAs. We have a tau siRNA program. Some of the unique aspects of Alector Brain Carrier are tunability and versatility in terms of how we're applying this. One of the key factors we see is the binding affinity, including to the shuttle technology that's being employed. A common shuttle is the transferrin receptor. That's, you know, used by, you know, the red blood cells to get iron into the brain and, you know, to get iron across the blood-brain barrier and the endothelial barrier.
We're basically using that, as others have, to get brain penetrance. However, the binding to that transferrin receptor is something that we can really carefully modify in a way to maximize the therapeutic benefit while minimizing safety concerns, such as anemia. That's one aspect. Another aspect is, you know, how we're able to customize the epitope as it relates to the efficacy piece and also how we're able to customize the effector portion of the construct. For example, the FC portion of an antibody and how that's potentially either increasing immune activity in certain settings where you want it increased, such as, you know, in the context of Aβ, where you want the immune system to come in and clear the plaque, or in other settings where perhaps you don't want an immune effector function at all because you're trying to minimize any safety concerns.
Versatility around these different pieces is a differentiator for us.
In the last minute we have, you know, such a lengthy and deep level of science has gone into the company. Obviously, the, you know, a couple of setbacks here and there, the macro environment's been challenging because the valuation doesn't really reflect any of that. Maybe you can just kind of set the stage in terms of, you know, it's easy sometimes for investors to view things as black and white. But in totality, validation, you know, is more than just a zero-sum game, right? As you get closer to data, you know, later this year, you know, maybe speak about the implications. You know, speak about the validation of the breadth of work that the company's done. And there, you know, there are ramifications beyond that.
Yeah, absolutely. So, you know, we do believe we're in a strong position. So we have, you know, $354 million in cash as of the end of the first quarter. And that's runway recently extended into the second half of 2027. So that's a full year beyond.