Alector, Inc. (ALEC) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the Alector call to discuss recent data presentation conference call. [Operator Instructions] I would now like to hand the conference over to your first speaker today, Michelle Corral, Vice President of Communications and Investor Relations. Please go ahead.

Thank you, Laurie. Good afternoon, and thank you all for joining us on today's call. I'm Michelle Corral, Alector's Vice President of Corporate Communications and Investor Relations. Today, we will be reviewing data presented this week at the Clinical Trials for Alzheimer's disease or CTAD and the Society for Immunotherapy of Cancer or SITC meeting. We have data this week from 4 of Alector's pipeline programs, and each of those presentations is available on the Investors section of the Alector website. On today's call, we have CEO and Co-Founder, Dr. Arnon Rosenthal; Dr. Sam Jackson, our Chief Medical Officer; as well as Dr. Daniel Maslyar, our VP of Clinical Drug Development. After prepared remarks, we will open the line for your questions. As a reminder, the information discussed during this call will include forward-looking statements, which represent the company's view as of today, November 12, 2021. We undertake no obligation to update or revise any forward-looking statements to reflect new information or future events, except as required by law. Please refer to today's press release as well as our filings with the SEC for information concerning risk factors that could cause actual results to differ materially from those expressed or implied by these statements. I'd like to now hand the call over to Arnon for opening remarks.

Thank you, Michelle, and good afternoon to everyone. Today, we are happy to review data from 4 of our immuno-neurology programs. As you recall, immuno-neurology is conceptually analogous to immuno-oncology. Instead of targeting a single disease pathology such as beta tau alpha-synuclein, we are recruiting the brain-specific immune system to simultaneously counteract multiple disease pathologies. We actually have an advantage offering in immuno-oncology since human genetics of node degeneration points us to the relevant immune checkpoint that could be targeted. Does -- all our drugs modulate targets that regulate the brain innate immune system and that also constitute genetic risk for an older generation. Our therapeutic goal is to repair and harness the brain immune system as a broad therapeutic lever to halt and reverse and ultimately prevent neurodegeneration. Because our targets are based on human genetics, we are also able to monitor the impact of our drugs during treatment using multiple disease-specific biomarkers that human genetics help review. The data presented earlier today at both CTAD and SITC highlight the opportunity that immuno-oncology offers. On today's call, we'll be reviewing the INFRONT Phase II study with our progranulin elevating antibody, AL001, a drug that is currently in pivotal Phase III. And we will review Phase I data for AL101, our second progranulin elevating antibody. We will review Phase Ib results for AL003, our candidate for Alzheimer's disease that targets SIGLEC-3, and we will also review preclinical data from our multi-SIGLEC inhibitors. As you may know, progranulin is an immune regulatory protein and a lysosomal chaperone whose deficiencies associate it with multiple neurodegenerative disorders in a dose-dependent manner. We have developed therapies that safely and persistently elevate progranulin in the human brain. The SIGLEC is a family of inhibitor immune checkpoint receptors that are expressed on the microglia brain immune system as well as on peripheral innate immune system cells. We have developed biologics cable of blocking the inhibitory activity of the SIGLEC checkpoint molecules. And because the SIGLECs are immune checkpoints for the central as well as the peripheral myeloid cells, we are advancing SIGLEC therapeutics for both neurodegeneration and cancer. In fact, we think that many of our innate immune drugs would be therapeutically similar to the anti-CD20 drugs that are effective both as cancer drugs and in multiple sclerosis. Daniel Maslyar, our VP of Clinical developers will start us off with a discussion on those SIGLEC programs. Dan is an oncologist, a Genentech veteran with decades of clinical drug development experience. He had been deeply involved in leading our innate immuno-oncologic and SIGLEC biology efforts. Following Dan's discussion, Sam, our Chief Medical Officer, will share data from our progranulin elevating program, 001 and AL101, after which we will open the line for Q&A. Then let me turn the call over to you.

Thank you, Arnon. It's a pleasure to be here today to introduce you to Alector's AL009 immuno-oncology program and share data from our AL003 Phase I clinical trial in immuno-neurology. Both AL009 and AL003 target Sialic acid-binding immunoglobulin-type lectins, or SIGLECs, for short. SIGLECs are a family of receptors that are predominantly expressed on myeloid cells such as macrophages and microglia, which are found in the brain. When bound to cell surface sialic acid glycans, SIGLEC expression regulates immune activity. A particular interest here at Alector has been the role of SIGLEC's planned immunosuppression. In the brain, we believe that unregulated SIGLECs may have a detrimental effect on the ability of microglia to do their job in maintaining brain function and health. And if we could decrease expression and reduce signaling, we may be able to increase microglia activity. This is a therapeutic hypothesis for AL003, which selectively targets SIGLEC-3 or CD33. In oncology, we know that SIGLEC Sialic acid-binding is associated with the evasion of tumor cells from the immune system detection and the indirect suppression of T cell function. Again, if we could broadly decrease SIGLEC immune inhibition, we might be able to increase the ability of the immune system to combat cancers. And perhaps more importantly, we will pursue this in a way that is differentiated from other immunologic approaches. This is the basis for our AL009 program. Today at SITC, we presented a poster characterizing AL009's in vitro and in vivo activity. AL009 is a unique model molecule with a special mechanism of action to fusion protein, to fusion protein that blocks ligand binding activity of multiple SIGLECs, and in doing so, acts as a checkpoint inhibitor to block immunosuppression for myeloid cells. Preclinically, we like what we are seeing. In vitro, AL009 led to dose-dependent increases in immuno-stimulatory molecules, including CD86 and TNF alpha as well as cytokine and chemokines while reducing CD163, which is a macrophage-specific marker associated with an immunosuppressive phenotype. In addition to this evidence that AL009 is repolarizing macrophages from an anti-inflammatory state to a pro-inflammatory state, we also observed evidence of increases in T cell function in the presence of myeloid-derived suppressor cells, or MDSCs. And this increase in T cell activity was at least tenfold greater than other immunologic agents that were tested. AL009 is a potent checkpoint inhibitor. Pharmacodynamic markers comparing AL009 with anti-PD-L1 showed similar levels of T cell activation between the 2 agents in mouse models. The activity of each agent was increased when used in combination. And we believe that this is linked with the evidence that we see with AL009's ability to influence the adaptive immune system through modulation of macrophages. We hypothesized that based on its distinct mechanism, AL009 could have greater success, either alone or in combination with existing immunotherapies, in tumors that have been unresponsive or refractory to standard treatment. In solid tumors that are resistant to treatment with standard immunotherapy, AL009 again demonstrated decreases in immune suppression and increases in immune cell activation. Across our in vivo studies, the addition of AL009 to anti-PD-L1 achieved greater effect in shrinking tumors than anti-PD-L1 alone. Based on these preclinical results generated to date, we're looking forward to taking AL009 into the clinic next year in patients with advanced solid tumors. Now turning our -- to our clinical stage SIGLEC-3 inhibitor for Alzheimer's disease, AL003, which is a monoclonal antibody is designed to decrease the cell surface expression and inhibitory signal of SIGLEC-3 and to increase the activity of microglia, thereby reversing inhibition of immune cell activity and restoring homeostasis in the brain. Earlier this week at CCAD, we presented results from a randomized placebo-controlled Phase I study of AL003. The Phase I study enrolled a total of 38 healthy volunteers in 6 active cohorts, testing single doses of AL003, and doses ranging from 0.05 to 60 mgs per kg, plus a cohort of 12 patients with mild to moderate Alzheimer's disease who received 2 consecutive doses of 15 mgs per kg of AL003. Overall, AL003 was well tolerated up to and including doses of the 15-milligrams per kilogram. Immune-related adverse events were observed at higher dose levels, including 2 that were attributed to study drug. Among the Alzheimer's patients,that were treated at 15 milligrams per kilogram, there were no adverse events associated with the study drug. AL003 is engaging target at well-tolerated doses. And we see evidence of AL003 engaging its target, SIGLEC-3, in both the single ascending dose and the multi-dose arms of the trial. And this was assessed by CD33 expression in peripheral immune cells. Also, pharmacodynamic effects in the CSF are demonstrated in these dose levels as well. The emerging profile supports continued study of AL003, and we anticipate advancing it into Phase II clinical trials. AL003 is partnered with AbbVie. And with that, I will turn the call over to Sam Jackson, Alector's Chief Medical Officer, for an update on our progranulin programs. Sam?

Thanks, Daniel, and good afternoon, everybody. I'm pleased to join you today to review the data we presented this week for AL001 and 101 at the clinical trials for Alzheimer's Disease, or CTAD meeting. I have the privilege of attending CTAD live, and it was very gratifying to be able to share these data directly with the clinicians and researchers in attendance. Starting with AL001. The Phase II INFRONT-2 clinical trial is an open-label study and was designed to assess the safety and tolerability of chronic dosing of AL001 for the treatment of frontotemporal dementia, a devastating form of early onset dementia that progresses rapidly and is usually fatal within 10 years of symptom onset. INFRONT-2 included 3 cohorts of FTD patients, a symptomatic FTD-GRN patients, symptomatic FTD-GRN patients and FTD-C9orf72 patients. Data presented today focused on the symptomatic FTD-GRN cohort. As of the data cut, we had 10 patients who completed 12 months of treatment. And for each measure, we have at least 9 FTD-GRN patients with 49 week assessments completed. Much of the following data will look familiar to the results presented at AAIC, and that's a good thing. Given the relatively small numbers of patients per cohort, the consistency and the totality of the data combined to give us confidence that 001 is working as intended. Now to review, let's start with safety. AL001 has been generally safe and well-tolerated in 27 patients exposed for a median duration of 12 months. While 3 patients in the FTD-GRN cohort experienced a serious adverse event, None of these events was related to AL001 and all but 2 treatment-related adverse events were mild in severity. Treatment with AL001 led to a rapid and durable increase in progranulin level, completely rescuing the progranulin deficiency that is causing the disease in these patients. At baseline, mean plasma levels of progranulin were 40.3 nanograms per mil, rising to 91.2 nanograms per mil. Similarly, in the CSF, we observed increases from a mean of 2.3 nanograms per mil to 4.2 nanograms per mil. Turning to discussion to key biomarkers associated with disease. We assess the effective AL001 treatment on biomarkers of lysosomal and complement function, key pathophysiological pathways in FTD that are impacted by progranulin deficiency. When compared to age-matched controls, the lysosomal proteins cathepsin D and LAMP1 and a component of the complement cascade C1QB were elevated in the CSF of FTD patients at baseline, indicating lysosomal dysfunction and aberrant complement activation are important in FTD. We observed a durable reduction in these 3 analytes in the CSF to near control levels after 6 and 12 months of dosing, suggesting that elevation of progranulin caused by treatment with 001 restores normal lysosome and complement function in these patients. Probably the most interesting new finding in this data set are the findings related to the biomarker GFAP, or glial fibrillary acidic protein, a marker of astrogliosis. Astrocytes cells in the -- are cells in the brain responsible for regulating and maintaining an optimal milieu for neuronal functioning. When there is insular injury to the brain due to an acute event like a trauma or chronic disease, astrocytes proliferate and become reactive in response, a process known as astrogliosis, for which GFAP is an acknowledged biomarker. GFAP has been identified as a marker in FTD as well and it is associated with disease severity and with faster rates of brain atrophy. As you would expect, GFAP levels in our FTD-GRN patients at baseline were elevated. Treatment with AL001 led to a marked decline in GFAP in both plasma and CSF, bringing levels in symptomatic patients down to those seen in patients without symptoms. In our Phase II symptomatic patients, the mean GFAP level in plasma was 339 -- excuse me, 330.9 picograms per mil. With AL001 treatment, mean GFAP levels at 49 weeks were 183.4 picograms per mil. The GFAP range at baseline in asymptomatic FTD-GRN participants was 101.2 to 228.6 picograms per mil. We observed a similar dramatic and sustained decrease in GFAP in the CSF from a mean of 14.1 nanograms per mil at baseline down to 9.9 nanograms per mil at 49 weeks. As a point of reference, the range for GFAP in the CSF of asymptomatic FTD-GRN carriers with 2.6 to 10.7 picograms per mil. This increase from baseline in GFAP suggests a reduction in astrogliosis. Together with the data on the improvement in liquid biomarkers, plus the slowing of ventricular enlargement and brain atrophy shown on MRI and reported at AAIC, provide us confidence that alters 1 is impacting the underlying disease. That confidence is further bolstered by the results from our measurement of clinical benefit using the CDR plus NACC FTLD sum of boxes at scale. This is an established assessment tool which evaluates clinical impairments in behavior, language and orientation, memory judgment and functional activities in trial participants, and it is the primary endpoint in our pivotal Phase III trial in FTD-GRN. Now since INFRONT-2 is an open-label study, we generated a matched control group by which we could assess the rate of disease progression. With access to the GENFI2 registry and using the well-established propensity score method, we identified 10 patients with GRN mutations whose baseline characteristics and importantly, whose baseline CDR plus NACC FTLD sum of boxes scores match the baseline of the symptomatic FTD-GRN patients in our Phase II trial. The matched control group was selected on a blinded basis, meaning we had no idea of the patient's change from baseline when they were selected. In the control group, the CDR sum of boxes scores increased by 6.4 points from baseline over a year, indicating rapid disease progression. In contrast, the annual change in the Phase II cohort was only 3.3 points indicating a 48% reduction in the rate of disease progression. All in all, these data are very encouraging. Today, FTD patients have no approved treatment options. And no hope of any slowing of the progression of their disease. If replicated in the ongoing INFRONT-3 Phase III clinical trial, these results would represent a clinically meaningful treatment effect. We started the INFRONT-3 Phase III clinical trial of AL001 in July 2020, and we are actively enrolling patients at more than 40 sites so far with frontotemporal dementia who are carriers of a GRN mutation. The randomized, double-blind, placebo-controlled Phase III study is intended to service our pivotal trial in the FTD-GRN indication and as such, will enroll 180 participants who will remain on treatment for 96 weeks. Enrollment is presently on track with our expectations. The primary endpoint of the pivotal Phase III trial is the effect of AL001 on clinical decline by utilizing the CDR plus NACC FTLD sum of boxes scale. The same scale on which I presented data today from our Phase II trial. Our next readout for the AL001 program will be from the FTD C9orf72 cohort, and we are aiming for a presentation of data in the first half of next year. C9orf72-driven FTD has several differences from FTD-GRN. Most notably, it is not driven by a genetic mutation that directly leads to a progranulin deficiency. While less is known about biomarkers in patients with C9orf mutations, we are hopeful that data from our open-label trial will provide us another opportunity to see if elevating progranulin can have an impact on neurodegeneration more broadly. Based on evidence and literature, we have reason to believe that increasing progranulin levels will have therapeutic benefit in numerous neurodegenerative diseases. We are developing our second progranulin-elevating therapeutic, AL101, with the intent of using it for broader indications, such as Parkinson's disease and Alzheimer’s disease. So its mechanism is similar, AL101 is a distinct molecular entity. It works in the same way by binding Sortilin, a progranulin degradation receptor to increase levels of progranulin by 2 to threefold. Earlier this week, we presented our first set of human data for AL101 from a Phase I single ascending dose study in healthy volunteers. 55 study participants were randomized to either placebo or single dose of AL101. The Phase I tested intravenous administration of AL101 at doses ranging from 6 mg per kg to 60 mg per kg as well as a single cohort of subcutaneously administered AL101 at a dose of 600 milligrams. Overall, AL101 was well tolerated. The adverse events that occurred were primarily mild or moderate, such as headache, 3 serious adverse events were reported. 2 of these were deemed unrelated to study drug, and the third was associated with an infusion site reaction. The study established that AL101 is getting into the brain and the central nervous system. And importantly, we observed positive evidence of target engagement, as single doses led to increases in progranulin levels in the periphery and in the brain. And this elevation lasted for a month. We are thus far encouraged by AL101's emerging profile and the potential for AL101 to be dosed subcutaneously, and we are continuing to look at this opportunity in the clinic. And with that, I'll turn the call back to Arnon.

Thank you, Dan and Sam, for providing an update on 003, 001, 101 and our innate immuno-oncology program, 009. It is really rewarding to see safety and activity with these programs as well as evidence of clinical benefits for 001. Today, our immuno-neurology pipeline includes 4 clinical stage candidates in 6 clinical trials. By the end of next year, we expect to have 7 therapies targeting 6 distinct diseases with up to 10 clinical trials running from first in human Phase I through Phase III, including 2 forms of FTD with progranulin mutations and FTD with C9orf mutations, ALS, multiple programs in Alzheimer's disease and programs in Parkinson's disease, as well as multiple types of solid tumors. In addition to the 09 programs that Dan described, we also have a 008 program targeting SIRP-alpha, which is being developing partnership with Innovent. I wanted to especially mention our TREM2 therapy, which target a key risk gene for Alzheimer's disease. The program is now in Phase II. And in Phase I, we have shown target engagement as well as effect on the brain immune system. Although we will have 6 programs in the clinic, next year our discovery efforts are also continuing with additional programs, so both neurodegeneration and cancer. And as I outlined before, we are really traversing between these 2 indications. I will now open the line for Q&A. And as a reminder, again, with me on the line are Daniel Sam and Michelle. Michelle?

[Operator Instructions] Our first question is from Matthew Harrison of Morgan Stanley.

Great. Two for me. So one, on 101, can you just talk about dose selection? And how much target engagement you think you need and sort of what doses and maybe more importantly, what frequency of dosing you think you can achieve now that you have some of the initial targeting data? And then second, could you just update us on where you are with C9orf patients in your progranulin programs and when we might see some more data from those patients?

Yes. Thanks, Matt. This is Sam, just in case everyone keeping track. I think from the standpoint of target engagement, we're pretty happy where we are with the dosing. I think in general, we're always balancing safety and efficacy. And we would like to find the target as hard as we need to with the dose we've chosen. With respect to C9orf, we are actively enrolling in the Phase II trial, and we are presenting these data in the next -- as Arnon said, in the first half of the year. Michelle, do you want to say anything else about the scheduling for that?

No, at this point, we can't. So the plan is to provide that data at a medical meeting. So abstracts are being prepared, submitted, et cetera, and we will definitely keep everyone updated as soon as we have acceptance and can share timing for that.

Yes, yes. I do also want to highlight that we did dose 101 subcutaneously in some patients. So we're very excited about the prospect of this medication being a subcutaneously delivered therapeutic. And obviously, that opens up a lot more access and convenience for our patients and the potential, although we haven't assembled the data here, for dosing that's different from the monthly dosing that we're currently understanding for 001.

And our next question is from Geoff Meacham of Bank of America.

This is Alex on for Geoff. And congratulations on the data. Can you give us your thoughts on the developmental time lines for AL001 in FTD? Can you give us any expectations of when we should see data? And then just kind of to follow up on the prior question, what data will you be sharing from AL001 in FTD patients with the C9orf mutation? And do you expect results to be in line with what you've seen with FTD?

Yes. Michelle, I think that one was for me. I'm sorry, I couldn't hear the first question, was that about 101 or 001?

001.

Yes, about the time line, the development time line.

Yes, yes. So for C9orf patients, we are presenting those data in the first half of this year, as I think we've already mentioned, we're actively collecting it and analyzing it now. And we're still actively enrolling patients in the Phase II trial. With respect to the time line, we are -- for 001 in FTD-GRN, we are continuing to enroll these patients, consistent with our estimates. And we really haven't commented publicly on our enrollment but it's certainly consistent with where we think we need to be in this rare disease.

And can you just elaborate on what data you'll be sharing with the AL001 with the C9orf mutation?

I think you're going to have to wait for the meeting, unless Michelle, you want to say more?

Yes. No, to Sam's point, there's not a ton more that we can share. We'll strive to do sort of be -- sort of similar to what you've seen us do this year with 001 and FTD progranulin. But C9orf is a similar but different beast. So we're looking at that and our team is really looking part of even what are the right biomarkers there. But target effects as well as CDR NACC and volumetric MRI are all things that we've definitely built into the study. So each, we're still in the process of utilizing. We can't really provide specifics, but striving to always share robust data sets.

Yes, ultimately, we are looking basically to show cognitive benefit in all the diseases. That's the ultimate provable endpoint. So we are measuring cognitive effect in all our clinical trials as part of our package.

Right, right. But I think everyone on the call probably knows that with small data sets, you want to tell a comprehensive story that involves the clinical effect, which is clearly the most important as well as the biomarkers that make the most sense in the context of disease. And I think, as Michelle and others have acknowledged, in C9orf, that context is probably different than it is in FTD-GRN. So we're not anchoring to specifics right now. Let's stay tuned.

And our next question is Neena Bitritto-Garg of Citi.

So just kind of a follow-up, I guess, to some of the previous questions around the C9orf72 patient data. Can you just remind us if you're planning on providing a natural history kind of comparison there as well like the FTD-GRN patients?

I think that we certainly hope to follow a similar course that we followed with FTD-GRN, namely contextualizing the data by doing a similar approach that you guys have seen with FTD-GRN. I will emphasize that this is -- this requires a great deal of analysis and thought and as well as collecting the data. So I'm not going to anchor on anything right now, but you can expect that there will be some context provided.

And our next question is from Yaron Werber of Cowen.

Great. I have just a quick question for 101. When you look at the subcu PK at the 600 it sort of aligns with the lower end of the PK on the IV side. And obviously, you want to develop that as a subcu, I imagine. How are you thinking about dosing, and can you push the 600 mgs higher?

Yes. Sam, do you want to take that?

I can answer a little bit. Sure. I'd love to. So if you look at the PK dosing and as it relates to the subcutaneous and the intravenous testing, one of the things that is always a struggle within dosage formulations and the strategies for dosing is whether or not you have requirement for peak dosing versus whether or not you have a requirement for area of threshold. And I think the subcutaneous dosing gives me actually great confidence that area over a threshold seems to be making the biggest effect because not only if you look at the PK dosing, but the pharmacodynamic effects that you're seeing within the CSF, the 600 milligrams per kilogram dose level does, I think, map reasonably proportionately for the dose on a dosage level as opposed to an exposure model. I think within that context, that gives us a lot of freedom in thinking about whether or not you need to really maximize your dosage to get an exposure or whether or not you can do subcutaneous administration. And I think the issues around subcutaneous -- for subcutaneous administration is really about formulation issues. Now we're in the Phase I study environment right now. And obviously, naturally, we're looking into formulations to improve it into a subcutaneous dosing regiment. So do I think it's reasonable and feasible to consider a subcutaneous dosing regimen for AL101? Yes, absolutely. I think it's a great question, and it really highlights the promise of 101.

Our next question is from Tom Shrader of BTIG.

This is Zhong calling in for Tom. And congrats on the data and the progress you guys made so far. So I had a couple of questions regarding the AL001, like biomarker data for GFAP. So regarding the GFAP as a biomarker like does the level of GFAP correlate with the disease progression? And then are there any hints from the patient data on GENFI database? And I have a follow-up after that.

Yes, I can take that one. So I can say that we don't have GFAP data from the GENFI database. And as far as correlation between the biomarkers in our data set and the clinical outcome, we would love to be able to do those kinds of mathematical manipulations, but we are still dealing with a pretty small data set. So I would hesitate to certainly imply any kind of linear relationship with one or the other. I think, clearly, we can say that there is an association, I don't know if we can put a number on how strong that association is because in our Phase II data set, we did see a pretty impressive clinical improvement, and we saw a marked decline in GFAP. Now when you look at the magnitude of that decline in GFAP, I do think -- don't hold me to this right now because I don't have all of it in front of me, but that's a pretty big decline. So one would expect perhaps that the association might be stronger there. But we don't have a large enough data set to do any of the math that you would want to do.

I see. And then as a follow-up, and then -- so in terms of like GFAP and astrogliosis, like how established is it as a mechanism of action? So does an increased level represent extent of the activation from the neuroinflammation or does it represent more of a repair mechanism as an injury response from the atrophy itself?

Yes, that's an interesting question. So -- So GAAP is actually a marker of astrogliosis, right? So the anger and the riling up of these cells rather than a marker of astroglial injury per se. -- right? So for astroglial injury, we might be looking at something like YKL-40. But for astrogliosis, we are -- we do consider GFAP more of that. So it's really a marker of the activation of the cells.

And our next question is from Paul Matteis of Stifel.

This is Katie on for Paul. We just had a quick question on AL003, and presenting the SAD/MAD data, and I know you guys announced you're moving into the clinic next year. Are you confident that you found the right dose to move forward? And are there any other details you could provide on potential design?

Yes, I think I can take a stab at that one. Michelle, have we discussed that yet, though, before I venture into the waters?

Yes, Not so much -- I mean, at this point, we're not providing specific timing as to when we would move into the next phase of study. We do feel encouraged by the data just presented though and continue to sort of plan for those next steps. And then, Sam, I think you can take -- that should be it for timing.

Yes. So the dosing, yes, we do think that we have dose that we show full target engagement, both in the periphery and in the brain, based on CSF sampling, of course, healthy volunteers and AD patients. And we think that the dose where we see full target engagement, there is no -- there are no adverse effects. And it's a sort of long-lasting target engagement that suggests that once a month treatment or even less frequently would be sufficient. So with regard to target engagement in the brain and periphery and safety, we think that we have the right dose.

Right. And I just want to remind everyone we are developing this molecule in conjunction with our colleagues at AbbVie. So we are in discussions with them with respect to aspects of the Phase II design.

And our next question is from Myles Minter of William Blair.

When I look at the CDR Plus NACC data that you presented today versus AAIC, say, I think there's 2 extra patients with data in there and 1 looks like they don't decline at all and the other looks like it declines, basically in line with the GENFI2 cohort. So can you tell me anything about those 2 patients that have difference, sort of GFAP rating, K sign or NfL levels and how they sort of responded to treatment over the course.

Yes. Miles, this is Sam. Thanks for your question. I think the point that we're trying to make is that when we added these 2 new patients, that we didn't really see a big change in aggregate. Now as you know, there are some -- patients will differ in their response. We have not -- we're still evaluating these data and trying to understand if there are all the correlations. I mean, I would love to be able to do correlational analysis, as another questioner suggested. But the data set is still pretty small. I think we can follow up at a later time to talk about those individual patients, if you'd like.

Okay . That's fine. And then maybe on 101, what was the rationale for doing the 15-minute slow injection on the subcutaneous dosage. That sounds pretty long to me, maybe that's just a function of an early-stage study, but a clarification on that would be great. And if that time is going to improve.

Right. Well, why don't I pitch that one over to Dan. Since we are discussing this.

it's a very reasonable question to ask. So really what that comes down to is the stages of development for CMC and formulation issues. So as we initiated in the study, to go into the clinic and IV formulations and the translation to subcutaneous. We are essentially using a larger volume of fluid for the subcutaneous administration just to see what the associations are for PK and PD interactions. Now that we have a lot of confidence in the relationships between the parcokinetic and pharmacodynamic interactions. And obviously, we moved forward with the formulation updates for subcutaneous administration. That's really what it comes down to is sort of a Phase 1 environment efficiency.

There are no further questions on queue. I will now turn the call over back to Michelle for his closing remarks -- or her closing remarks.

Thank you. Thanks again, Laurie, and thank you, everyone, for joining us today. As a reminder, the data we reviewed on this call are posted to the Investors section of the Alector website. We are looking forward to participating in the Stifel Healthcare Conference next Monday, and we hope to see many of you there or are on the virtual road in the near future. That concludes our call. I hope everybody has a great weekend, and thanks so much.

And this concludes today's conference call. Thank you for participating. You may now disconnect.

Thanks everyone.