Conference. My name is Ananda Ghosh. I'm an 8VC associate. With that said, I would like to welcome Gary Romano, the CMO, and Marc Grasso, CFO of Alector, and we can start the first thing.
Great, thanks for having us.
Thanks for having us.
Sure. Yep, you know, Alector has become synonymous with neuroimmunology, and so can you, if you can briefly discuss the vision of Alector concerning neuroinflammation and neurodegenerative diseases, that would be a good introduction.
Yeah. Yeah, thanks, Ananda. So, Alector is founded on the vision that, you know, is really ten years in the making, and this is based on genome-wide association studies and other work that has shown that genetic variants that are associated with neurodegeneration can cluster in the genes that are expressed in the microglia, which is the immune cell of the brain. It's really this founding premise and in other contexts for neurodegeneration, that Alector has really advanced a number of novel first-in-class programs. We can talk about them, that includes our progranulin franchise, which is now in pivotal phase III, fully enrolled, for frontotemporal dementia in patients with a GRN mutation.
We are also fully enrolled for the most advanced TREM2 program in clinical development, and we can talk about that. And we have a number of other programs as well, including the blood-brain barrier technology platform. So the company, you know, all of this is based on that fundamental premise around neuroimmunology and the ability to basically restore the healthy functioning of the brain's immune system to prevent or counteract the progression of neurodegenerative disease.
Okay, I see. You know, with that said, maybe we can switch to latozinemab. Can you briefly talk about latozinemab and the FTD program, especially concerning the importance of progranulin biology in FTD and other neurodegenerative diseases?
Yeah. So latozinemab, this is our most advanced program. It's in a pivotal phase III study that's completed enrollment. It completed enrollment at the end of last year. And what we're doing with latozinemab through the inhibition of sortilin is restoring progranulin levels back to normal. And specifically in the setting as mentioned of frontotemporal dementia patients with a GRN mutation. These are patients with one bad copy and one good copy of the gene that expresses the protein progranulin, and with one bad copy, you have half the normal levels. And what we're doing through the inhibition of sortilin is restoring those levels back to normal, and this is something that we've advanced through a phase II study. We presented the phase II data.
This was the basis of the recent grant of breakthrough designation from the FDA. That was also the basis of a significant deal with GSK, where they paid us $700 million upfront. There's $1.5 billion in development and commercial milestones, and we're advancing this program together through the phase III. The phase III is to support potential full approval in the setting of this very significant unmet need. There's no approved therapies for this disease, and it's, you know, a significant opportunity for us.
Great. You know, let's talk about the biomarker data from the INFRONT-2, be it progranulin or NfL, or most importantly, probably GFAP. It indicates that AL001 hits the target. What are the indications from the biomarker data so far, you know, with respect to the pro?
Yeah. I can take that one. So, so the phase II study that you're referring to was intended to look for signals of safety, target engagement, as you mentioned, and also effects on pathophysiologic biomarkers of the pathophysiology of FTD and clinical outcomes. And so, for target engagement, we measured CSF and plasma progranulin levels and demonstrated that we saw an increase, a two- to threefold increase in progranulin levels in both CSF and plasma, which is, which returns in haploinsufficient patients. These are patients with a GRN mutation of half the normal levels of progranulin. That two- to threefold increase increases progranulin levels to normal, and it was sustained over the course of a year or more with data.
That was target engagement or quote, "hitting the target." Next, we had biomarkers, and we looked at biomarkers that measured changes or treatment-related effects on the pathophysiology of FTD, and that includes, so if you look at pathology of FTD patients, they have lysosomal dysfunction, they have immune dysfunction, they have astrogliosis, and they also have neurodegeneration and loss of brain volume, so the biomarkers there were. We looked at biomarkers for all of those different functions. We also had a clinical outcome measure called the CDR plus NACC FTLD sum of boxes, just rolls right off the tongue.
That's a clinical dementia scale that is designed specifically to measure changes in FTD patients who have behavioral and language dysfunction, and what we saw, I think what was really most remarkable about that study was that even though it was a relatively small study with you know 12 to 10 patients in 12 to 20 patients or so in the arm in different arms, every biomarker and clinical outcome assessment moved in a direction that you would expect if latozinemab was slowing this the pathophysiology of disease or the clinical progression of the disease. And so to your question what's the relevance of all that or why is that important to us? Why are we excited about that?
Because it gives us confidence that our phase III study, which is, instead of, you know, 10 to 20 patients, 100 patients, a placebo-controlled study, that, you know, makes us feel that we are in good-- you know, we expect to reproduce those findings and have a which will provide a path to a pivotal, a potential BLA approval.
You know, given the FDA's indication that it would consider the effects of latozinemab on plasma and CSF progranulin levels and other relevant fluid biomarkers, what does it mean for the program, and why is the feedback encouraging?
Yeah, so what you're referring to is our recent type B meeting we had with FDA, which we were granted on the basis of that approved the-
Breakthrough.
Breakthrough designation. Thank you. Breakthrough designation. And that was to explore you know strategies for our BLA submission late next year. But FDA we reached alignment with FDA on a couple of important points. One was that they would accept the data on changes in plasma and CSF progranulin levels as confirmatory evidence. And that's important because it means that in addition to that if you have a clinical effect, that this confirmatory evidence on the basis of the target engagement would increase the certainty of that it's truly efficacy. So that's important.
Secondly, we aligned with them on those, on some of those biomarkers that I just mentioned in the last, the last question, specifically on GFAP, which is measure of astrogliosis, on volumetric region of interest volumetric MRI, which measures brain, brain atrophy, and on NfL, which neurofilament light, which measures neurodegeneration. And they, they agreed that each, each, each of those could be considered as supportive evidence of a, of a, of effect on clinical outcomes. And so again, that, that really, again, reinforces or increases our confidence that since we've already have data on those biomarkers from our phase II, that were we to reproduce that data, we'd be in a very strong position for a to for a potential yeah approval.
I've asked these questions before also, but just for this audience, given the result of the trial, will you be willing to go for an accelerated approval pathway, followed by a full approval pathway?
Yeah, so the question is whether or not we'd go for an accelerated approval. We have confidence that we're gonna have the data that we need for a full approval, and that's our priority, and that's our plan. That said, I mean, if for one or more reasons, the clinical outcome measure underperforms, we are encouraged by this interaction because we had it with FDA, because, you know, there is the potential that since FDA endorsed these biomarkers for the purpose of supporting clinical outcome, they may also consider them as potentially biomarkers on which we could base an accelerated approval approach.
But that is really a backup situation for us if the clinical outcome measure doesn't work.
Got it. Great. So you know, we'll switch gears to the TREM2 program now. You know, so let's start with why is TREM2 an attractive target for Alzheimer's disease, and how it is differentiated from other anti-amyloid therapies currently approved?
Yeah. So why are we excited about it, and how does it juxtapose to the anti-amyloid antibodies? So triggering receptor that's expressed on myeloid cells or TREM2, it's a phospholipid receptor on the surface of microglia. That senses damage. And so when TREM2 engages with its natural substrates, which are substances that suggest that there's injury, like misfolded proteins or cellular fragments or other substrates, it then initiates a signaling pathway that allows the microglia to adopt a defensive posture to or a defensive as a posture to to protect against disease or these insults.
And our hypothesis is that AL002 increases the signaling in TREM2, and that this will, in essence, restore microglial function in these patients and lead to this defensive posture. And that includes a number of downstream mechanisms of TREM2, not only clearance of misfolded proteins like amyloid. Yes, that's part of it, but also maintenance of healthy synapses, maintenance and repair of the blood-brain barrier and the vasculature, support of astrocyte and oligodendrocyte function, and other mechanisms. So we really see this mechanism as being potentially affecting, you know, clearing misfolded proteins. We'll know about that soon. But also these other mechanisms. We really think it goes beyond amyloid clearance or clearance of one misfolded protein.
That said, we also think that this mechanism could be complementary to the anti-amyloid antibodies. And so we are considering that it could be potentially either additive or even synergistic with anti-amyloid antibodies. And so our plans going forward as we're planning what to, you know, what comes next, would be, you know, if we have positive data, clearly, we'll have a phase III program for monotherapy of AL002. But we're also looking at add-on or combination type of treatment with anti-amyloid antibodies.
Our you know, we've talked to a lot of folks in the field about this, and I think our leaning, where we're leaning is to have an add-on where you would start with an anti-amyloid antibody that would lower brain amyloid levels, and that would potentially mitigate against the ARIA. There is the potential, of course, because both our mechanism and AL002 and anti-amyloid antibodies cause ARIA. If you were to lower amyloid first with an anti-amyloid antibody, that would mitigate against the additional ARIA from AL002, and then AL002 could be started as a maintenance therapy after anti-amyloid lowers amyloid level.
Interesting. Now, at the AAIC, you shared the baseline data from the INVOKE-2 trial. You know, what is the significance of the data concerning the program?
Yeah, so that was our. We reported at AAIC on our baseline characteristics. The main finding there was, just to jump to the chase, that it showed we enrolled the population that we intended to enroll, which is early Alzheimer's disease. That was demonstrated by showing that on clinical severity, which is, you know, measured by clinical measures, we had about two-thirds patients had MCI and one-third had mild AD. And then also, looking biologically at the amyloid PET centiloid mean values were just around 100, which is also consistent with an early AD population. But we fell right in the middle between donanemab and latozinemab on the mean centiloid values. And that's why is that important? Because we, you know, we think that the early AD population is where we probably have the best opportunity to demonstrate treatment effect on disease progression.
You know, what is the data that might be most important for you in the phase II program of AL002, which probably, you know, allows you to decide to move to the phase III?
Yeah. So what is, what does the win look like for us there? What are the data we're most excited about? Well, as I mentioned, this was a phase II study. It was. It's a dose-ranging, a biomarker-rich study that included a number of biomarkers and clinical outcomes. And the intention of AbbVie and Alector when they designed the study was to have it be a, you know, as a phase II study, that the totality of the data would provide evidence of slowing of disease progression, you know, both whether it's measured by a combination of clinical and biomarker endpoints. So that's really what we're looking for the study to produce.
Actually, you know, we actually are fortunate that in the interim, since the study was designed, and now there's been a lot of advances in biomarker technology. As you know, there now are these phospho-tau, you know, plasma biomarkers and plasma phospho-tau biomarkers. So in addition to measuring clinical outcomes with a variety of clinical outcome measures and amyloid PET and tau PET, we now have these plasma biomarkers, which we'll have on every patient in multiple time points. So I think we're gonna have an even more robust package than was originally, you know, designed. And so what are we looking for? We're looking that we see a slowing of disease progression as measured by some combination of clinical and functional and biomarker readouts.
Yeah, so, and that, you know, that, that's really what, what we're looking for. I mean, we're powered for a 40% treatment effect. We could see. We saw treatment effects in a range of what they saw with the donanemab and latozinemab. You know, they would very likely be statistically significant changes in that 20, that's, you know, 20%-30% slowing. But let me just be clear, we're not, you know, we're not gonna make our decision one way or another on a p-value, on the CDR because which is our primary endpoint, for the reasons I just explained.
Got it. So we'll switch gear again now. You know, the blood-brain barrier technology is definitely becoming more and more crucial for CNS companies. Can you tell us about your ABC technology and what will be the future goal for the technology and its application with respect to Alector's pipeline?
Yeah, thanks, Ananda. We're very excited about the progression of ABC, or Alector Brain Carrier. It's a very timely and distinct approach from our standpoint. One of the things that differentiates our approach versus others that are out there is the versatility, and that relates to a number of different aspects. It relates to versatility around the payloads that we can incorporate. It also relates to the versatility of the actual mechanism we're using. And so, we are looking at both transferrin as well as CD98 heavy chain mechanisms. And CD98 heavy chain, transferrin is more well understood, which is...
Utilizing, you know, the iron transport system, and that's expressed on a number of different cell types. CD98 is a heavy chain, is an amino acid transfer mechanism, and they have different profiles, and both, we think, are going to be important, but in different contexts. The other aspect of versatility is being able to tune things like affinity, avidity, and specific context as it relates to different payload types, and we're looking at a range of different opportunities, whether that's antibodies, enzymes, proteins, nucleic acids. So being able to basically customize in each of these different payload types and disease settings, we think is very important. So, you know, more to come on that. We have a number of disclosed programs and undisclosed programs, but we're excited about the progression of the platform.
That brings to the final question. You know, we have not discussed much of the AL101 program before. I was thinking, you know, if you can speak about AL101 program, and which has been validated by the GSK collaboration.
Mm-hmm.
What is the therapeutic hypothesis supporting the trial? You know, how is the program designed and, with respect to the endpoints and biomarkers, and what do you intend to learn from the program?
Yeah, yeah. Thanks, Ananda. So AL101 is our second progranulin elevating program. It's also an antibody approach, has a longer half-life than latozinemab, and is positioned for the larger market opportunities, including Alzheimer's disease. So this is enrolling in a phase II study. So to your question, you know, what is the support for this? Well, we know that progranulin is a genetic risk for Alzheimer's disease, and we're seeking to do in this phase II is to demonstrate that elevating progranulin is actually gonna slow disease progression. So this is a multi-dose phase II that's measuring slowing of disease progression as CDR sum of the boxes as the primary endpoint. But also it's similar to TREM2. It's a biomarker-rich study.
We're measuring a number of other cognitive and functional endpoints over the treatment period, which is 76 weeks. And you know, we're doing this together with GSK, and as mentioned, the study is enrolling now, and we're looking forward to continuing to progress AL101.
Great. And, you know, so now I think the floor is open for the questions. If you have any questions, feel free.
In delivery, various mechanisms such as transferrin, is that already a new approach, or what do you think about that?
Is it an R&D-heavy approach in terms of the different payloads and mechanisms? Yeah, it's something that we're, you know, Alector has a history, and, you know, it's a company, you know, as mentioned, it was founded ten years ago, and we have a significant research team and effort. And, you know, you know, it, it's something that, you know, we've built over time. We've only begun talking about it publicly a little bit more recently. But yes, it's a significant effort from a research perspective.
Did the AL101 program be appropriate for AD?
Correct. Yeah, AL101 is being developed in early Alzheimer's disease.
But you're now in phase II, correct?
Correct. AL002 is in another phase II study, and that's targeting TREM2 in early Alzheimer's disease. And these are-
AL101.
AL101 is with GSK, as is latozinemab, so the progranulin elevating programs are partnered with GSK. And then AL002 is part of an option deal with AbbVie, where AbbVie will have the opportunity to opt in after the completion of the phase II data that Gary walked us through, which is expected end of this year. They'll have a period of time where they can decide if they're gonna opt in to move that program forward into a phase III. If they opt in, it's a $250 million payment to Alector, and then they take on the phase III, and then we would share in the profits 50/50.