All right, welcome to the Cantor Global Healthcare Conference. I'm Pete Stavropoulos, a biotech analyst with Cantor. With us, we have Alector, a company I cover, and I'm pleased to introduce the CEO, Arnon Rosenthal, and the CFO, Marc Grasso. So, welcome, and let's start off with a brief introduction of yourselves, followed by a description of the company, why Alector was founded, and you know, what the thesis of the company is. You wanna?
Sure. Yeah, pleasure to be here. Thanks for having us, Pete. Marc Grasso, the Chief Financial Officer. Been at Alector almost three years now, and very excited about the progress we're making.
I'm Arnon Rosenthal. I'm the CEO, co-founder. I was at Genentech for 16 years, and then started two additional companies, Rinat Neuroscience, which was acquired by Pfizer at the time, and Annexon Biosciences, which is a public company that Pete is also covering. Alector was created with the idea of developing a different therapeutic strategy for dementia and neurodegeneration. Instead of going after misfolded proteins, which most other companies are doing, we are recruiting the brain's own immune system to counteract multiple disease pathologies. In this respect, we are conceptually similar to immuno-oncology. What revolutionized cancer treatment was that instead of trying to destroy tumors directly with chemotherapy, radiation, we are now recruiting the immune system to do the work for us.
So immune checkpoints, CAR T, are really ways to recruit the immune system to counteract cancer, and we are again recruiting the immune system to counteract multiple disease pathologies in Alzheimer's disease and other neurodegenerative disorders.
All right, thank you. You know, Alzheimer's disease, it's a space that's exploded with interest, with the accelerated-
Right
... approval of aducanumab and lecanemab, lecanemab and donanemab, sorry.
Yes.
These are the, you know, they're targeting various forms of amyloid beta, but you're focused on other targets. You know, do you have two molecules in the clinic? You know, what are some of the key learnings from those programs, meaning the lecanemab and donanemab?
For me, the two key learnings are that Alzheimer's disease is a tractable disease, means that it can be treated and hopefully cured, and that going after a single misfolded protein, the Abeta, is not sufficient. That sort of it will lead to a very modest clinical benefit. It seems as if there is a glass ceiling for the magnitude of the therapy with anti-Abeta antibodies around 25%-30% slowdown in cognitive decline over 18 months. Our approach, which recruit the brain immune system, has a much broader aspect. It treats multiple disease mechanisms, and as a result, we ultimately expect our drug to have better efficacy and more durable efficacy compared to anti-Abeta drugs.
Right. You know, and your most advanced program is a TREM2 agonist, activation of TREM2. And so, you know, you have a key readout coming on later on this year in Q4. You know, can you just describe that target and why you chose to pursue it in Alzheimer's?
Yes. So TREM2 is the most prominent immune stimulatory molecule or immune stimulatory receptor for the microglia, for the brain immune cells. And there are very strong genetic evidence linking it to dementia and Alzheimer's disease. So if you don't have TREM2 at all, you develop dementia by the age of forty at a 100% penetrance, and die shortly after. If you have one of forty partial loss of function mutations in TREM2, you increase the risk of developing Alzheimer's disease by three- to fourfold. And conversely, people that have higher than normal level of TREM2, at least as measured by soluble TREM2 in the CSF, are largely protected from Alzheimer's disease, and the rate of their Alzheimer's disease progression is significantly delayed.
They see slowdown in cognitive decline, slowdown in brain tissue loss, delayed age of onset, better survival with AD, delayed buildup of Abeta and tau. So all aspects of Alzheimer's disease progression seem to be impacted by the level of TREM2. And again, TREM2 is only expressed on the immune cells in the brain, and all its activity, its protective activity, are mediated by impact on the immune cells in the brain, and it impact the proliferation, survival, migration, and multiple aspects of the immune cells' functionality. So we chose this target, again, because it was the most prominent risk gene for Alzheimer's disease beyond the Abeta-related risk genes. And that it's consistent with our hypothesis that recruiting the immune system to counteract disease, multiple disease pathologies will have significant benefit.
Right. So TREM2 activation does activate microglia. You know, can you just sort of walk us through the different types of microglia that exist, and what exactly, what impact does TREM2 have in terms of the type of microglia?
There is still sort of debate how many different types of microglia exist. Some people identify dozens of different types of microglia based on gene expression signatures. I mean, if you look very broadly, there are probably three classes of microglia. There are resting microglia that are just sort of surveying the brain. There are modestly activated microglia. These are the disease-fighting microglia that counteract pathologies. And then when microglia become stressed or overwhelmed by disease burden, they become hyperactive and could be damaging. And the disease-fighting microglia can further be divided to multiple subclasses. There are at least four subclasses of disease-fighting microglia that are, again, defined by gene expression signatures and some activity.
We think that TREM2 basically induces the conversion of resting microglia to what's called transient microglia that give rise to the disease-fighting microglia. We think that TREM2 can facilitate the generation of four different types of disease-fighting microglia. If you have more disease-fighting microglia, the chance that these disease-fighting microglia will become overwhelmed by the disease and become hyperactive and pathological is significantly reduced. We really bring more soldiers to the fight. We bring more potent soldiers, better-trained soldiers. Basically, we have better ability to counteract multiple disease pathologies and reduce potential that the microglia will become overwhelmed and become pathological.
Okay. And, you know, in terms of, you know, you're constantly stimulating new microglia activation. You know, is there some type of equilibrium or, you know, homeostasis in the level of microglia?
Yes, I mean, so there is always homeostasis on the total number of microglia, and in most cases, the majority of microglia are still resting microglia. Only a small portion of the microglia are going in a way to fight, to deal with the pathology, and TREM2 again changes the balance of this homeostatic to disease-fighting microglia, and again, tilt the balance towards better ability to counteract the disease.
All right. You know, going back a little bit, a comment that you made, so soluble TREM2 levels. You know, they're associated with benefit in AD patients, you know, meaning it's associated with slower progression-
Mm-hmm.
to MCI and AD. You know, and so, question is, is soluble TREM2 important? Like, is there pharmacological properties?
Yeah. So from our standpoint, we view soluble TREM2 as it's a cleavage product from the TREM2 that's bound to the receptor. And largely, it's just a measure of how much activity you're having constitutively at the receptor. So from our standpoint, you know, it can be valuable as a biomarker of activity, and we see that in the context of, you know, when we bind the receptor, we cause internalization of the receptor and a temporal reduction of soluble TREM2. And that's a marker of pharmacological activity for our drug. And you can also see it constitutively, the cleavage product can be increased, and that's seen in constitutively more active TREM2 signaling as an indicator of protection in the setting of Alzheimer's disease.
But again, there's a distinction there between the pharmacologic activity and the constitutive cleavage of the product.
Yeah, basically, we don't think that soluble TREM2 on its own is a significant component in fighting Alzheimer's disease. We think it's primarily a biomarker and a way to mitigate premature activation of microglia by soaking or sort of binding low level of ligands and preventing it from interacting with the receptor, the membrane receptor. But there are reports that it does maybe have independent protective function. We don't think that these are meaningful.
Okay. All right, just moving on to the phase II study, INVOKE-2. You know, design seems extensively detailed, you know, sort of size to capture, you know, signals of activity and possible efficacy. Again, we're gonna get a first look of activation, TREM2 activation in AD patients, next quarter. You know, just give us a brief description of the study design.
Yeah, sure. So, that's right. We are guiding to data in Q4 of this year, later this year, and, you know, very excited. This will be the first, you know, randomized placebo-controlled data for TREM2. The study is designed as a multi-dose placebo-controlled study. So there's three active doses, and there's placebo. There'll be just over 250 completers is our estimation at this point. We've completed enrollment. It's a common closed design, and what that means is that the last patient in is treated for 48 weeks, and every patient prior is treated up to 96 weeks, and this allows us to capture as much data as possible over this time period.
And we'll be looking at CDR-Sum of Boxes as the primary endpoint and measuring slowing of disease progression over the treatment period. And we'll have patients at 48 weeks, 72 weeks, and 96 weeks. And then we have patients that complete that portion and go on to an extension study as well, and we'll have some of that data as well.
... Okay, and, in terms of powering assumptions?
So powering, we're powered to detect initially, as the study was designed, a 40% slowing of disease progression over the treatment period by dose arm. We should note that the top two doses overlap in PK, and we've pre-specified the opportunity to look at those on a combined basis, which would enhance powering as well. We think with you know the patients we've enrolled, we can likely detect down to a mid-twenties percent slowing of disease progression and still potentially have it be statistically significant.
Combination will be 45, 60?
Correct.
Not the 15.
That's right.
Okay. I'm sorry, I may have missed it, and the powering is up to 85%, or?
Yeah, we're-
Okay.
Yeah, that's correct. Yeah.
All right. Sorry.
Yes.
In terms of a breakdown of the proportion of patients in each group at forty-eight, seventy-two, ninety-six weeks.
Yeah. So we'll have all patients at 48 weeks, and then we'll have approximately half of those patients at 72, and about a third at the 96-week.
Okay. And then, in terms of, expectations, you know, what would you consider, positive?
Yeah. So from our standpoint, what we're looking to see is the slowing of disease progression and supported by biomarkers. Doesn't necessarily have to be statistically significant from our standpoint. In fact, you know, given a trial this size, you know, to us, you know, what we'd like to see is, you know, some measure of slowing of disease progression. Doesn't, as I mentioned, have to be necessarily statistically significant, but also supportive of biomarkers, whether that's, you know, amyloid, whether that's tau, whether that's these other measures of microglial activity.
All right. I guess one of the key questions is: Does AbbVie share your perspective on this?
We can't speak for AbbVie directly. It's obviously up to them. However, in the conversations we've had to date, we think they're thinking about it in a similar way as are other key opinion leaders in the field.
Okay. And if you did have to choose, you know, two, three biomarkers, to see you move in the right direction, which ones would they be?
Yeah. Basically, the most validated biomarkers for-
Mm
... Alzheimer's disease are A beta and tau. GFAP has recently been used for lecanemab. But again, we are looking at the totality of the data. It's a novel mechanism that may be represented by different biomarkers compared to anti-A beta drugs. So I think we will want to see, yes, a positive trajectory for cognition and sort of more than one biomarkers moving in the right direction to be excited.
Are your expectations for A beta being sort of removed...?
Again, our mechanism does not, is not dependent on Ab eta. Meaning as we have incidences of ARIA-like events, which suggest impact on Ab eta, but we think that we could see clinical benefit even with a modest reduction in beta amyloid. We know biologically that the microglia can inactivate A beta, not by just removing it, but by containing it. They surround the A beta plaques. They prevent A beta plaques from leaching toxic aggregate and killing surrounding neurons. You can have clinical benefit even in the presence of A beta, because the A beta become inert following, like, encapsidation by microglia. We could possibly see very modest effect on A beta reduction by PET imaging, but much more significant clinical benefit.
Okay. And then, in terms of, the baseline characteristics at INVOKE, this summer, you did announce the baseline characteristics. So how do they sort of fall between, the donanemab and, lecanemab studies?
Very... Yeah, very, very consistent. So, you know, we believe that we've enrolled the relevant population for studying a drug like this. It's very consistent in terms of the staging of patients. All the patients were confirmed to have amyloid beta by PET imaging. The Centiloid level was very consistent with what we're seeing with lecanemab and donanemab. And also the staging of patients from a symptomatic perspective, mild cognitive impairment, and early Alzheimer's disease. So, you know, we feel confident we've enrolled the relevant population.
Okay. And, last year, not last year, 2023, at AAIC, you know, you did announce sort of blinded data from INVOKE-2. You know, you had observations of ARIA-like events. You know, just walk us through how you're actually thinking about that data.
Yeah, so from an ARIA perspective, you know, it is in the vast majority of patients just an imaging finding and not a symptomatic finding. In the patients that do have symptoms, you know, most of those patients, thankfully, the symptoms are mild, and in the very few patients that have more, you know, significant symptoms, we're able to manage that through, you know, removal of therapy temporarily, and there's also extensive monitoring that's been put in place, so the other side of ARIA is that, you know, we and others in the field view it as an indication that there's some biological effect happening.
As you know, ARIA has been seen with the anti-amyloid A beta antibodies and has been associated with plaque removal. And it may be that that's what's occurring with our therapies as well.
... And then to manage the ARIA, I know that you had made protocol adjustments earlier on, and also how you're looking at sort of looking to further reduce ARIA in the long-term extension.
Yeah, so as a you know matter of precaution in the phase two study because we saw that the you know more significant ARIA was occurring in the patients that were homozygous for APOE4 so that we removed those patients from the ongoing phase two. We still have the patients that were homozygous for APOE4 we removed. We're keeping the heterozygous APOE4 and the non-APOE4 carriers so that was one aspect, and then as mentioned as well so we have ongoing MRI monitoring and there's also you know for patients that do have you know significant symptoms we're able to you know remove therapy and/or reintroduce therapy at a lower dose titration.
Sorry.
Yeah. So one of the way to try to mitigate ARIA is to introduce a dose escalation. So all the patients starts at low dose, and incrementally that sort of they reach their maximal dose. So we'll see if that helps to mitigate the severity and the prevalence of the ARIA at the time.
Okay. And just talk a little bit about the long-term extension, how, you know, patients do remain blinded, or at least, the original treatment remains blinded, and what you can do with that data.
Yes. So every patient that completed the main trial can elect to continue treatment to the long-term extension. So far, over 95% of the patients elected to convert, and that's, again, a sign that the drug is not detrimental, that patients and possibly their caregivers think that there may be some benefit, so that's a good sign for us. In order to maximize the validation of the data that we will derive from the long-term extension, we kept the dosing blinded to the participants. So people sort of don't know if they were on placebo before, and they don't know what dose they were on.
So until the end of the long-term extension, the patients will be blinded to the treatment effect, and we think that that will keep the trial more objective and the data more validated. Like recently, there were several cases where drugs received accelerated approval based on blind and long-term extension. Tofersen was one of these, so we really wanted to keep the long-term extension as blinded and objective as possible to really be able to use the data as part of regulatory process.
Yeah, and Marc, AbbVie deal structure?
Yeah. So, it's an option deal, is the way it's structured. They've paid us about $250 million so far, both in significant upfronts and also milestones for, you know, the commencement of the extension study that Arnon was mentioning, also adding more patients to the phase 2. At the end of the phase 2, which again is, you know, end of this year, we're expecting data Q4 of this year. They will receive a proof of concept study package from us, and that will be the basis for their potential opt-in.
If they choose to opt-in, which would be a $250 million payment to Alector, they would then take the program on for further development, including presumably onto a phase 3 and eventual approval. It is a 50-50 profit share worldwide, and you know, we're working very closely with AbbVie, you know, going into this data event and the proof of concept study package.
Okay, great. You know, we have about five or so minutes left. Let's switch gears, and talk about your sortilin antibody, AL001, latozinemab. And just sort of give a... You know, walk us through the mechanistic rationale for actually targeting sortilin for FTD.
So we have two additional clinical programs, so we have a total of three clinical programs. The non-TREM2 clinical programs are programs that are intended to elevate the level of secreted immune regulatory molecules called progranulin. Progranulin has a sort of major function in lysosomal activity, in promoting the survival of nerve cells, and also in promoting normal beneficial activity of the immune cells in the brain. And like with TREM2, progranulin has very strong genetic linkage to neurodegeneration. In humans, there are three types of genetic loss-of-function mutations. People that don't have progranulin at all develop dementia by their teens at 100% penetrance, and again, seizures, blindness, and short lifespan.
People that have one good and one bad copy of progranulin develop frontotemporal dementia before the age of 60, and this is the target population for our drug. In addition, there are mutations in progranulin that reduces the level by 10%-15%, and this is enough to increase the risk of developing Alzheimer's disease, Parkinson's disease, and other types of neurodegeneration, but significantly. Progranulin appear to be a universal risk gene for neurodegeneration, and because loss of function or decreased level is always detrimental. We developed a drug that elevates progranulin, and our drug does it by blocking a degradation receptor for progranulin, a receptor called sortilin. Sortilin is a receptor that takes progranulin from the extracellular milieu, and bring it into the cells for lysosomal degradation.
There's human genetic data and subsequent mouse genetic data, that if you block sortilin, you can elevate the level of progranulin chronically, both in the brain and in the serum, by two- to threefold. So our drug mimics the human genetics. It blocks sortilin, prevents it from interacting with progranulin, and the result is that there is chronic elevation of progranulin in the brain and in the serum. We have shown sort of chronic elevation in multiple types of animal models, mice, rats, non-human primate. We showed in an animal model for frontotemporal dementia that the drug can reverse behavioral deficits. In healthy volunteers, we showed again chronic elevation of progranulin.
In phase 2 open label study in frontotemporal dementia patients with progranulin mutation, we were able to show, again, normalization of progranulin throughout the treatment period, normalization of multiple disease biomarkers, slowdown in brain tissue loss, and 48% slowdown in cognitive decline over a 12 months period, which is almost double what you see with anti-beta antibodies, for example. So we had a very extensive open label phase 2 data, which the FDA reviewed and allowed and sort of gave us breakthrough therapy for this drug. And with this data, we embarked on a phase 3. We completed the recruitment of phase 3, and we expect the pivotal data that, if the data are positive, will lead to a BLA filing by the end of 2025, early 2026.
All right, great. And the last minute that we have left, and thank you for that overview of our FTD program. If we're sitting here from a year from now, and I ask you, you know, what have you accomplished, or what value-creating events have you accomplished, what would you like to say?
Yes, I would like to say that we'll have a transformative therapy for Alzheimer's disease that will be significantly more potent than, and durable than current therapy. A therapy that can work either as standalone or in combination with anti-beta drugs, and would possibly transform the dementia field in a way that's similar to how immuno-oncology transformed oncology field. So we think we could have a transformative drug for Alzheimer's disease that could also be applicable for other major types of neurodegenerative diseases. We could have a second drug that address dementia by a different mechanism, and it could really provide relief for frontotemporal dementia patients. Again, this is a type of disease for which there is no disease-modifying or symptomatic drugs. And we'll have possibly indications of efficacy for a third drug in Alzheimer's disease.
So we'll have, I think, three transformative drugs for neurodegeneration and dementia that could change the field of brain disorders, as well as an advanced pipeline of drugs for other types of neurodegenerations, like Lewy body dementia, Parkinson's disease, ALS. Yes, we want to create ultimately a world where degenerative brain disorders are like the realm of the past.
So a lot going on. I look forward to hearing continued updates throughout the year. Unfortunately, we didn't get a chance to talk about some of the earlier stage programs and platforms, the Alector Brain -Carrier platform, but we will in the future. So thank you very much-
Great
... for joining us.
Thanks to you.