Wonderful. Thank you guys all for joining us, and for those joining us from the webcast. Really appreciate the time this afternoon with the CEO from Alector Therapeutics. And-
Good.
really appreciate your joining us for this conversation. Maybe just at a high level, could you talk about what Alector is and with respect to the particular competencies that you guys have that drive your business forward?
Yeah, absolutely. So our mission is really to eradicate brain disorder, degenerative brain disorders. And the approach and the competence that we have developed is to integrate human genetics, immunology, and neuroscience to develop a new class of drugs. So whereas everyone else in the field is going after misfolded proteins to cure neurodegeneration, so you know, there are dozens of drugs going after Aβ for Alzheimer's disease, after tau for Alzheimer's disease, after alpha-synuclein for Parkinson's disease. We have taken a different approach. We are recruiting the brain-owned immune system to counteract multiple disease pathologies. So we are really following what happened in oncology. In oncology, what really revolutionized treatment was that instead of killing cancer directly with irradiation or chemotherapy or toxin-conjugated antibodies, we are now recruiting the immune system to do the work for us.
So all the checkpoint molecules, the CAR T therapy, are really recruiting the immune system to go after cancer. We are conceptually doing the same thing in neurodegeneration. We are recruiting the brain-owned immune system to go after multiple disease pathologies. And so, so as a result, again, we developed competence in immunology, and sort of all our drugs are based on human genetics, and we have insight in neuroscience to really know how-
Mm-hmm.
What target to go after for what disease?
Perfect. We'll go into them in more depth, but if you could, just provide us an overview of the pipeline that you guys have, and with maybe a focus on what the kind of next updates are gonna be.
Sure. So we now have three late-stage clinical programs. We have a TREM2-activating antibody. TREM2 is a major risk gene for Alzheimer's disease, and we've just completed recruitment in a phase II double-blind and placebo-controlled trial, and we expect data in the next six months. And if the data are positive, we think that this could transform the field because it will be a fundamentally different approach to treat Alzheimer's disease. We have a phase III drug for frontotemporal dementia, which is the second largest form of dementia for people under the age of 60. As I said, we just completed recruitment, and we expect data by the end of 2025, and this will be a pivotal study which would follow, if the data justify that, BLA and-
Mm-hmm
... subsequent approval, and we received breakthrough therapy for this drug recently. And we have a phase II drug in Alzheimer's disease, which is again another progranulin elevating drug, which we just sort of started phase II recruitment, and, hopefully, we'll complete somewhere around 2026 or 2027. So we have three clinical programs. We have a pipeline behind it that's focused on the larger neurodegenerative diseases, different types of Parkinson's disease-
Mm-hmm.
-genetically stratified types of Parkinson's disease, Lewy body dementia.
Perfect. Maybe let's dig into AL002, which you mentioned is a TREM2 agonist. Maybe first, just explain that mechanism and the relevance it has in Alzheimer's disease.
Sure. So for many years, people thought that Alzheimer's disease is a disease that's focused on damage of nerve cells. So in Alzheimer's disease, you see neuronal death, you see significant reduction in the complexity of connections between nerve cells. Normally, each nerve cell is connected with 10,000 other nerve cells. In Alzheimer's disease, this complexity can go down by up to 50%. So people thought that it's a pure neuronal disease. But the recent human genetics suggested that actually, even though the pathology is a neuronal pathology, what causes the disease is actually dysfunctional immune system.
And so the majority or a large number of the 100 or so risk genes that have been identified in Alzheimer's disease were shown to be, in a way, immune checkpoints for the immune system in the brain, the cell type called microglia. And among this risk gene, the most prevalent gene that was identified is a single transmembrane receptor called TREM2. So TREM2 leads to neurodegeneration in an allele copy number-dependent manner. If you don't have TREM2 at all, if both copies of TREM2 are dysfunctional, you develop dementia by the age of 40 at 100% penetrance. If you have one good and one bad copy, partially bad copy of TREM2, that's one of, I think, over 60 point mutations now been identified, you increase the risk of developing Alzheimer's disease by up to threefold-four fold.
Conversely, people that express higher than normal level of TREM2 appear to be protected, they have reduced risk of Alzheimer's disease, and if they develop Alzheimer's disease, the rate of cognitive decline is lower than in people that have lower level of TREM2. The age of onset is delayed, the buildup of Aβ and tau is delayed, the brain tissue loss is delayed, the conversion from mild cognitive impairment to full Alzheimer's disease is delayed. So there is very strong human genetic that this single transmembrane receptor that expressed only on microglia plays a key role in Alzheimer's disease. And because the human genetic shows that loss of function is detrimental, where gain of function is protective, we developed a drug that mimic the gain of function feature.
Mm.
So our drug is activating TREM2, and it does it both as a standalone drug and it synergizes with the natural ligands of TREM2.
Okay. That's super helpful. As you think then about the preclinical and potentially early clinical data that you all have generated with your agonist, talk to us about how that kind of genetic correlation has translated into seeing clinical changes in patients.
So in preclinical context, we've seen efficacy in multiple models for Alzheimer's disease. We've seen efficacy in multiple models of multiple sclerosis. In human, in phase I, we saw that our drug is able to engage the target and recruit the microglia immune cells in the brain. Means we saw a dose-dependent saturable effect on multiple microglia activation biomarkers. So based on the animal model data, the human genetics, and the phase I data, we went to phase II, which again, we'll have data by the end of the year. In phase II, we see that the drug is well tolerated, and the intriguing thing is that we see incidences of ARIA.
Mm.
Means, ARIA is, or ARIA-like event. ARIA is MRI-based imaging abnormality that was reported with anti-Aβ drugs. And so far, all the anti-Aβ drugs that showed clinical benefits were associated with increased of this MRI imaging abnormality. And the features of the MRI imaging abnormalities that we see are indistinguishable from the-
Mm-hmm
... abnormalities that were seen with anti-Aβ antibodies. So the simplest explanation is that we are somehow removing Aβ, although the trial is still blinded, and we have to-
Sure.
-see by the end of the year.
Perfect. That's a great segue to my next question, which is: we obviously are expecting this clinical data from the phase II later this year. Maybe first, just could you provide an overview of some of the key trial design parameters in that study?
Sure. So this is a placebo-controlled, double-blinded study with close to sort of 400 patients. It's a 4-arm dose. There is a placebo dose and three dosing arms, low, middle, and high. It's a common close design trial, so by the end of the year, we'll have patients that were treated for 12 months, for 18 months, and for 24 months. And people who completed the trial duration will move voluntarily to a long-term extension-
Mm-hmm
-period. The trial measures five different cognitive and activity of daily living readouts. The primary readout is the CDR-SB, which is what's used for additional clinical measures. In addition, and tau by PET imaging.
Mm-hmm.
Aβ 40, Aβ42, multiple type of phospho-tau by-
Mm-hmm
in the serum and the CSF. We are measuring multiple biomarkers for neuronal damage, for as sort of astrocyte dysfunction. Again, periodically, and we measuring very extensively changes in the protein configuration before and after treatment. So by the end of the year, we expect that the totality of data, again, combinations of multiple clinical readouts, imaging, and biomarkers, will really tell us if we have an active drug.
Okay. So maybe a couple additional questions on the trial design. As you thought about patient selection and inclusion criteria, what's the patient population that you're going after with this study?
It's an early Alzheimer's disease, like with CDR global score between 0.5-one.
Mm-hmm.
It's somewhere in between lecanemab and donanemab, so it's mild cognitive impairment to early Alzheimer's disease.
Okay.
Even though we focused on early Alzheimer's disease, we think that because of the broad mechanism, the drug would be able to to-
Mm-hmm
... to be effective in both early- and late-stage diseases.
Sure
Unlike anti-Aβ antibodies. But the trial design is again similar to what is seen with anti-Aβ antibodies with regard to patient-
Perfect
- baseline.
It's obviously going to be a data-rich study. You listed a number of endpoints. But as you think of which ones will be most informative, as you think about progressing this program forward, are there a couple that you're most focused on? Or where you think you can see the greatest changes?
Yeah, we think that the clinical readouts will be really, really important, the CDR Sum of Boxes. We need to see at least positive trend in these-
Mm-hmm
... measurements. We think that tau reduction would be really important, so I am looking forward to see these two things. And again, for tau, we are looking both by PET imaging and multiple serum and CSF phospho-tau subtypes, like phospho-tau 181, phospho-tau 217, which means, which just again represent what you see in the brain. So I think clinical read, tau and Aβ, I think.
Perfect. Then from a safety perspective, you obviously referenced ARIA. Is there anything else you're monitoring from a safety point of view?
Yeah, we are monitoring a lot of things. We have a safety committee that is unblinded to the data and meets every sort of quarterly, and they are looking at all safety features-
Sure.
- including, the treatment effect on cognitive-
Mm-hmm.
- decline. So yes. ARIA by MRI, very sort of frequently, we are looking at effect on the treatment effect on cognition.
Mm-hmm.
We look at, yes, all the other safety features. We don't see any drug-related, like, meaningful adverse effects.
Yeah.
The safety committee so far did not see any-
Yeah, really?
-adverse effects. Yes, and also, like, incidentally, in 90%, over 90% of the patients that completed the trial and could elect to move to the long-term extension-
Yeah
- elected to move to the long-term extension study. So this suggests, again, that there are no adverse effects that prevent people from being treated and that people may think that there may-
That was gonna be my next question. Very good. Perfect. So as you think about the phase II results and what, like, a good outcome would be, I guess, how are you and also your partner in AbbVie, thinking about what kind of results would, you know, allow for, like a go decision versus a no-go decision?
So as you mentioned, this study or this program is partnered with AbbVie as a 50/50 sort of profit share worldwide, and AbbVie will have an opt-in decision to make by the end of, like, once they see the data by the end of the year. And I think that the consensus or the agreement between us and AbbVie is that we want to see positive, at least positive trend in multiple aspects. We want to see positive trend in the clinical readouts-
Mm-hmm.
- and we want to see positive trend, positive trend in the imaging and soluble biomarkers.
Okay.
So like consistent positive trend in multiple features of the disease-
Yeah
would be exciting for us, I mean.
How long after the data come does AbbVie, AbbVie have to kind of make a decision on this?
AbbVie has 90 days after they get the opt-in package. By the end of Q1, I think 2025, they will have to decide.
Okay.
And if they decide positively, it is associated with $250 million dollar payment, opt-in payment, and then they are taking over the phase III-
Mm-hmm
- execution. And again, it's a 50/50 worldwide profit.
Okay. Pending the decision to move forward with the program, how are you thinking about development strategy in Alzheimer's disease, particularly given it's something of an evolving landscape right now?
Yes. So I think that the key issue will be whether you can develop a standalone drug-
Yeah
- or whether you have to start considering combination therapies. I mean, the phase II or the standalone treatment, we think that, the phase III also will likely be a standalone, but we most likely will have an arm with a combination therapy.
Sure.
Like, there is a natural sort of possibility for combination with an anti-Aβ drug. What the anti-Aβ drugs do, they just mark sites of Aβ plaques, and then they recruit the immune system to excavate, to remove the Aβ.
Mm.
So anti-Aβ drugs are completely dependent on the brain immune system for any efficacy. There was an anti-Aβ antibody that Roche had developed with the antibody region that recruits microglia was mutated and was inert, and this drug was completely inactive. So there is no question that you need active recruitment of the microglia, the immune cells, to be effective. And basically, anti-Aβ drug mark the site for excavation, and we enhance the number and the potency of the excavator, the microglia.
Mm-hmm.
So there is really a natural combination, and I think a lot of companies are excited about this possible combination, including AbbVie. AbbVie is developing an anti-Aβ drug-
Mm
- that I think is going to read by the end of the year. So again, there will be a possibility, combination is needed.
Okay. And then I guess remind us, you talked a little bit about it, but the structure of the deal with AbbVie, if you could just kind of walk through the key parameters of that agreement. And then I think you mentioned already the next milestones, but certainly there's quite a few.
So the deal was signed as a, actually a preclinical program. We actually didn't even have a drug lead when we signed the deal. It we received at the time $220 million upfront payment, and AbbVie, during the trial execution, participated also with additional funding to support the long-term extension, to support recruitment of additional patients. So they gave us additional, I think, something like $30 million in a way, in milestones during the trial. And now that the trial is about to be completed, we are agreeing together on the content of the opt-in package, and we reach consensus on this.
Sure.
Again, once they receive the package, either at the end of the year or very early next year, they will have 90 days to decide whether they are opting in. If they are opting in, they will take over the phase III-
Mm-hmm.
-the manufacturing, and, there will still be a committee that like-
Mm-hmm
Share the development. And we are already planning a sort of the phase III.
Okay. Maybe switching gears to the latozinemab program and the progranulin franchise, and maybe more broadly, let's start with frontotemporal dementia. What is it? How is it caused? And how many patients are there?
Frontotemporal dementia is a very aggressive form of dementia. It progresses up to 3x faster than Alzheimer's disease. It hits people under the age of 60. Whereas in Alzheimer's disease, the main feature is cognitive and memory decline. In frontotemporal dementia, the major features are behavioral disinhibition.
Mm-hmm
... and in a sort of speech abnormalities and less like cognitive deficit. But again, it's a very little disease. People die within seven-10 years once they are diagnosed, and it unfortunately hits people sometimes as early as in their thirties and forties. And there are both sporadic forms and genetic forms of the disease. And one of the main genetic forms of the disease, about 10%, 5%-10% of all the frontotemporal dementia patients, is caused by loss of function mutations in a secreted immune regulatory protein called progranulin. So people that have one good and one bad copy of this progranulin gene show 50% or less of the normal level of this protein, and they practically invariably develop the disease.
In total, there are about 160,000-
Mm-hmm
frontotemporal dementia patients worldwide, and 5%-10% of these have this progranulin mutation.
Okay. So you mentioned that latozinemab is designed to increase progranulin, and that has relevance-
Yeah
-in the disease. So maybe you could walk us through the data that you've shown to date in terms of how latozinemab works in patients.
Because loss of function of progranulin is associated with frontotemporal dementia, it's also associated with actually practically every other neurodegenerative diseases.
Mm.
So modest loss of function of progranulin is associated with Alzheimer's disease, with Parkinson's disease, with LATE, which is a form of dementia caused or associated with TDP-43 pathology. It's associated with accelerated progression of ALS. So progranulin is an immune regulatory molecule, secreted immune regulatory and lysosomal chaperone that seems to be a universal risk gene for Alzheimer's disease. And since loss of function causes the disease, we developed a drug that elevates progranulin, and we did this by blocking a degradation receptor for progranulin. So conceptually, what we are doing in this system is similar to what SSRI are doing. So SSRI, like Prozac, block the reuptake of neurotransmitters, and by that increase the level of neurotransmitter that's available to neurons in the neuronal milieu. We are doing the very same thing.
We are blocking the reuptake of and degradation of progranulin, and by this, we elevate the level of progranulin that's available for nerve cells by twofold - threefold. So when we block the level, the degradation of progranulin, we showed in animal models and in human that we consistently elevate the level of progranulin in the brain by twofold. And in a phase II open label study, we were able to show that this elevation is associated with normalization of multiple disease biomarkers, with slowdown of brain tissue loss, and possibly most importantly, a slowdown in cognitive decline of close to 50%. And again, this was a small open label study that compare historical control patients to our treated patients. But this data was sufficient for the FDA to award us a breakthrough therapy.
The data were considered by the FDA, sort of quite valid.
Great. So obviously, you referenced some of the data points, but maybe you could expand a little bit on what that phase II study showed, particularly with respect to the differences versus natural history controls. And I'd be curious if you could also talk to, you know, the fidelity across patient populations, such that you believe this natural history control is a good replication of a placebo group.
So first, we looked at biomarkers before and after treatment in the same patient, so that's independent of historical control. So if you look at patients, you see elevation of multiple lysosomal biomarkers. Progranulin is a lysosomal chaperone. It enhances lysosomal function. So if you don't have progranulin, there is compensations in the lysosomes to elevate multiple lysosomal proteins, like different types of cathepsin. You also see elevation of complement proteins. Microglia, when they don't have progranulin, they are stressed because their lysosome is not functioning, and part of the stress or inflammatory mediators that are secreted as a result of the stress are complement proteins that actually end up destroying synaptic connections. So they see elevation in disease patients, you see elevation of lysosomal proteins, you see elevation of complement proteins.
We showed that with treatment, we normalize more than, like, nine different lysosomal and inflammatory proteins. Again, this is in the same patients before and after treatment. So in addition to looking at cognitive decline and brain tissue loss, we looked at historical control, and we matched patients based on the level of cognitive decline at baseline, and then based on the level of neurodegeneration biomarkers, like neurofilament.
Mm.
Based on age, gender, the subtype of frontotemporal dementia that we had, and this was all done blindly, and we identified control patients blindly, and then only after we identified the control, we looked at the rate of their cognitive-
Mm.
-decline.
Okay.
This historical control patients show decline of about 6.2 points over 12 months, whereas our treated patients show about 1/2 of this decline.
Okay.
And similarly, when you look—we look by volumetric MRI, the rate of brain tissue loss, both in the ventricles, which is basically the open space in the brain, that sums all the brain tissue loss and areas of interest, we saw sort of slowdown in brain-
Okay
... tissue loss. So again, you know, I mean, it's an open-label study.
Sure.
There's a lot of skepticism, but the FDA reviewed this data and...
Yeah
... so that it's, they are strong enough to allow us breakthrough there.
Yeah. On the back of this data, you have a phase III study that's ongoing. Talk to us about the key kind of parameters around that study and when we'll get the next data readout.
Yeah. So we have completed recruitment for a pivotal phase III study. It's, I think, 103 symptomatic patients and 16 pre-symptomatic patients that are mutation carrier. It's a 96-week-long study. The main clinical readout will be the CDR and NACC FTD. Like, it's a CDR that's tailored for FTD. It's the same as Alzheimer's disease, but with two additional measurements for behavioral and speech. So that's a clinical readout that was agreed by the FDA and by the European Regulatory Agency. We are measuring tissue brain volume over time. Again, the idea is if we have an effective drug, the rate of brain tissue loss will slow down. We are measuring multiple biomarkers. For example, in the phase II, we were able to show normalization of GFAP, which is, again, inflammatory astrocyte biomarkers.
It's elevated in FTD and with treatment, we show normalization. We are measuring neurofilament. So we have multiple clinical readouts, imaging readouts, and both serum and CSF biomarker readout, and the FDA agreed that sort of the integration of this data could be sufficient for approval.
Okay, very good. You also have AL101, which is similarly targeting progranulin. Maybe how is that drug designed to differ from latozinemab, and why does it matter in the context where it's being studied?
AL101 is an antibody drug, again, that blocks the degradation of progranulin. Mechanistically, AL101 and AL001 are very similar. AL101 has a different pharmacokinetics. It's a longer-acting drug.
Mm-hmm.
So you can either change the dosing regimen for less frequent, or you can reduce the dose, and we decided for the Alzheimer's trial to reduce the dosing regimen.
Okay.
The scientific rationale for treating Alzheimer's disease with progranulin elevating drug is both human genetics and animal models. Human genetics shows that even a modest reduction in progranulin genetic mutation that reduce the expression of progranulin by 15%, increase the risk of Alzheimer's disease. Progranulin is one of the official risk gene for Alzheimer's disease. Animal model studies show that elevation of progranulin, even beyond normal level, is protective.
Mm-hmm.
So we are basically, again, testing this progranulin elevating hypothesis in phase II. And again, the drug is blocking progranulin degradation, and it has a longer half-life than-
Sure... Could you just remind us of that phase II study? What are the endpoints and patients you're looking at, and when will we get a clinical update there?
So it's, it's a similar study to what we did with AL002, the TREM2 activating drug. It's, it's a study with about 282 patients. It's a 3-dose arm study. It's 18 months long study. The, the readouts are gonna be, again, CDR Sum of Box plus-
Mm-hmm.
I think four other clinical measurements for activity of daily living, PET imaging for Aβ and tau, multiple soluble biomarkers. So it's generally a typical Alzheimer's study.
Perfect. So I think you're planning to spend more time on this at an R&D day next week, but could you just talk high level about the rest of your pipeline with particularly a focus on, you know, how you think about the assets or targets you pursue, and where you think Alector is best positioned to kind of solve these problems?
Yes. Next week we are gonna have a webinar on our blood-brain barrier technology, and you're all invited.
Mm.
We are now integrating blood-brain barrier transport technology to many of our drugs. Blood-brain barrier technologies enable, like, enzyme replacement therapy for brain disorders, protein replacement therapy for brain disorders, improvement in antibody access to the brain, and even non-protein therapeutics like ASO and other nucleic acid therapies with enhanced brain penetrance. So you'll hear again in the seminar a little bit about our next generation drug candidates. We are disclosing two programs on Parkinson's disease.
Mm.
One is a GCase enzyme replacement therapy. GCase is a lysosomal enzyme that is mutated in about 10% of Parkinson's patients and in about 12% of Lewy body dementia patients. So we think that enzyme with brain-penetrating enzyme replacement therapy could be beneficial-
Mm
... for a large portion of Parkinson's and Lewy body dementia patients. We are working on another Parkinson's drug, targeting GPNMB. GPNMB is a risk gene for Parkinson's disease. And again, there is a protective and risk alleles, and we are mimicking with the drug, the protective allele.
Mm.
This will be more likely for sporadic Parkinson's disease.
Mm.
So, we have a pipeline of genetically validated, human genetically validated targets, drugs for both Parkinson's, additional drugs for Alzheimer's disease.
Mm-hmm.
Lewy body dementia is something that we work on. We are doing work on multiple sclerosis, sort of not from the immune suppression aspect, but from myelin-
Okay
... replacement aspect. And we work on ALS. So we have a pipeline of drugs that, again, everything is based on genetic human genetics that sort of increase the probability of technical success-
Yeah
... and in many cases, we integrate our blood-brain barrier technology into this pipeline.
Okay. So then with that in mind, again, the robust discovery activities that you have going on, how should we think about the right cadence for new INDs in a given year from Alector?
Just long term, we want to have at least one IND annually, maybe more than that.
Okay.
And-
Okay. Last question, it's biotech cash runway. Where are you? When, when are you funded until?
We are funded through 2026. This is two years beyond our AL002 TREM2 data.
Mm-hmm.
A full year beyond our 001 data.
Yeah.
We are gonna be very close to the phase II in, with the AL101 Alzheimer's data.
Mm-hmm.
So hopefully we can squeeze three clinical readouts with our runway, plus sort of our pipeline drug.
Yeah.
This is excluding any milestones or payments from large pharma or any other fundraising.
Perfect. Well, thank you so much for joining us. Great to have you all as well. Great. We'll wrap it up there. Thank you.
Thank you.