Ladies and gentlemen, thank you for standing by. Welcome to Phase 2 Chronic Spontaneous Urticaria and Atopic Dermatitis Results. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to turn the conference over to Robert Alexander, Chief Executive Officer. Please go ahead. All right, thank you, operator. I'd like to thank everybody for joining our call today. Before we get started, a reminder that we will be making forward-looking statements, so please refer to our SEC filings for a description of our risk factors. Joining me today in the room are our CFO, Baird Radford, our Head of Research, Brad Youngblood, our President, Adam Tomasi, our Chief Medical Officer, Craig Patterson, and our Head of IR and VP of Finance, Alex Schwartz. Do we have the slides cued up? Okay, sorry, folks. I think we're having a little bit of technical difficulty with the slides. So, folks, we're trying to get our slides up on our side. Please bear with us. Okay, I think we're ready. All right, so, next slide, please. Next slide. Okay, in terms of the agenda, we'll have. I'll turn it over to Craig here momentarily to go through the top-line results of the AD and CSU study. Baird will then go through the restructuring of the company, and then lastly, I'll give an update on our AK006 program. Okay, Craig? Yeah. Good morning. I'll begin with our Phase 2 study of lirentelimab in moderate to severe atopic dermatitis. This was a double-blind, randomized, placebo-controlled study in subjects that had chronic atopic dermatitis that was present for at least three years. Requirements for study entry included a baseline EASI score of at least 16, involvement of at least 10% body surface area, IGA score of three or four, and subjects were required to be inadequately controlled by topical treatments. We did include a proportion of subjects with prior biologic treatment. We randomized 131 subjects, 1:1, to receive 300 mg of subcutaneous lirentelimab every two weeks or placebo, and we enrolled these subjects from 53 sites in the U.S. and Germany. Our primary efficacy endpoint was the proportion of subjects who achieved an Eczema Area and Severity Index score of a 75% reduction at week 14. Key secondary endpoints included a% change in EASI from baseline to week 14, and the proportion of subjects who achieved an IGA score of zero or one, and at least a two-point improvement from baseline in IGA, again, at week 14. Next slide, please. Our baseline demographics and patient characteristics were overall well-balanced between active and placebo, and generally consistent with other studies in moderate to severe atopic dermatitis. Next slide. This is our primary efficacy analysis, which was the proportion of subjects achieving at least a 75% reduction in EASI score from baseline. As you can see, we were numerically superior to placebo, but this difference was modest and not statistically significant. Placebo response rate was reasonable and consistent with other studies in atopic dermatitis. Next slide. One of our pre-specified secondary endpoints was the percent change in EASI score from baseline, shown on the right, and we were also showing absolute change from baseline as well. There was a small numerical advantage for lirentelimab, but it was not statistically significant. Next slide. Our study included a randomization strata for baseline IGA 3 and IGA 4 to ensure that there were not more patients with a higher inflammatory burden, that is IGA 4, in either active or placebo. One of our pre-specified analyses was to evaluate the change in EASI score in the higher inflammatory burden IGA 4 group, as well as the IGA 3 group. We observed no differences in the IGA 3 group. Interestingly, we observed a greater percent reduction in EASI score in the lirentelimab subjects with baseline IGA 4 that just reached statistical significance. We We also evaluated itch as a pre-specified exploratory endpoint, with the proportion of subjects demonstrating either at least a three or at least a four-point reduction from baseline. Using the patient-reported PPNRS, or numeric rating scale, we observed trends in the data that favored lirentelimab, but these did not quite reach statistical significance. Next slide, please. Moving on to Phase 2 study of lirentelimab in Chronic Spontaneous Urticaria. Once again, this was a double-blind, placebo-controlled, randomized trial for subjects with active, moderate to severe symptoms. CSU was required to be present for at least six months prior to screening, and they had to be refractory to antihistamines at labeled doses. They were required to have a UAS7 score at baseline of at least 16 and a hive severity score of at least eight. We included patients with prior biologic treatment. 127 patients were randomized 1:1 to receive either 300 milligrams of subcutaneous lirentelimab every two weeks or placebo, and we enrolled these subjects from 56 sites in the U.S., Germany, and Poland. Primary endpoint was the change from baseline in UAS7 score at week 12. Key secondary endpoints included the absolute change in the itch severity score, which is one of the components of the UAS7, absolute change in the hive severity score, which is the other component of the UAS7, and the proportion of subjects who achieved a UAS7 score of zero. Next slide, please. Baseline demographics and patient characteristics in our CSU study were generally well balanced between the groups and similar to what we have noted in other CSU studies. Next slide. The primary efficacy analysis was the absolute change in UAS7 from baseline to week 12, and there was no difference for either absolute or percent change as shown. I will note that we had a relatively low placebo response rate in this study, and it was in line with a number of other reported CSU studies. Next slide. We pre-specified several responder analyses as secondary or exploratory endpoints. Shown here are those subjects with a UAS7 score of less than or equal to six and a UAS7 score of zero. Neither of these were statistically significant. Interestingly, all four subjects that achieved complete response with a UAS7 score of zero were on lirentelimab. Next slide. We also evaluated the components of the UAS7, which were itch and hive scores. Both of these showed what might be a trend in the data favoring lirentelimab that was not statistically significant and not of a compelling magnitude. Consistent with previous subcutaneous studies and IV studies using lirentelimab, we saw a rapid and robust depletion of eosinophils. Next slide, please. Next slide. Overall, the safety profile of subcutaneous lirentelimab was consistent with previous sub-Q studies, as well as IV studies and other indications. Most common adverse events were injection-related reactions, with approximately 18% of subjects on active experiencing an injection-related reaction versus about 7% overall on placebo. Thank you. Thanks, Craig. Good morning, everyone. I want to quickly provide an update on a few key elements of our financials. In our press release earlier today, we reported a restructuring to significantly reduce operating expenses that will, in turn, extend our cash runway into mid-2026. From a strategic perspective, this will allow us to focus on, one, fully funding our Phase 1 AK006 clinical development beyond the completion of a randomized, double-blind, placebo-controlled study in Chronic Spontaneous Urticaria. And two, fund additional advances in preclinical programs. The extension of our cash runway has allowed us and required us to take several decisive actions, including halting lirentelimab-related spending within clinical, manufacturing, research, and administrative functions, and reducing our workforce by approximately 50%. The urgency of these actions is even more important in the current market environment, and the management team is committed to executing the restructuring plan. These actions will allow us to trim our costs and extend our cash runway well past our key Phase 1 AK006 milestones and into mid-2026. Looking deeper into the 2024 cash flows, I want to flag a few items for you. First, we exited 2023 with approximately $170 million of cash and investments. Second, we anticipate that our restructuring activities will result in the use of approximately $30 million of cash in 2024, with the majority of this paid in the first half of 2024. Third, we anticipate that the cash used to fund our ongoing business operations after completing the restructuring activities will be approximately $55 million-$60 million. In an effort to avoid any confusion, we anticipate that the restructuring activities will result in higher levels of cash burn in the first half of 2024, before we see the benefits of the cost-cutting efforts over the second half of 2024. We anticipate that our business plan will allow us to exit 2024 with an estimated cash and investments balance totaling approximately $81 million-$86 million, and setting us up for a cash runway into mid-2026. As for our key AK006 milestones, we remain committed to developing novel treatments for patients with inflammation conditions and have an opportunity to demonstrate potential success in CSU. We expect to provide data in healthy volunteers in the second quarter of 2024, and to have top line data in patients with CSU at year-end 2024, meaning that at the time of the top line CSU data, we anticipate having over a year of cash and investments. Given this cash runway and the current market conditions, we have no plans to raise additional capital until after we report AK006 top line data in patients with CSU. Now, Robert will share additional information regarding our AK006 program. Okay, thanks, Baird. Go ahead and click next slide. So, since we introduced the AK006 program a year and a half or so ago, one of the questions we commonly get is: How does AK006 compare and contrast to lirentelimab? And I think that's probably a question that's gonna be front of mind given the data that we just released. And we just wanna emphasize several things. One is that AK006 targets a different receptor with a different underlying biology. And the bottom line is that Siglec-6 is a more potent inhibitory receptor than Siglec-8. And really, what that means is that Siglec-6 has a larger inhibitory footprint inside the cell than does Siglec-8, and it intersects or modulates or regulates a lot of key cellular activities, and we've listed those here. So from, on the receptor side, Siglec-6 appears to be a much more potent receptor. On the drug side, there are really two key differences between AK006 and lirentelimab. One is that AK006 has a long residence time on the cell surface. And during our antibody campaign effort, when we were developing antibodies to AK002, Siglec-6, looking at over roughly 1,000 different clones, what became clear was the higher the residence time, the more potent the inhibitory activity. So that's one key difference. The other key difference is that AK006 induces ADCP, or antibody-dependent cellular phagocytosis. So AK006 has the ability to reduce mast cell numbers, whereas lirentelimab does not. So the next two slides will all describe some of the detail about the receptor and then some additional detail about the antibodies. So what you're looking at here is a protein interactome. What we're showing are proteins that associate with Siglec-6, proteins that associate with Siglec-8, or proteins that associate with both of those receptors. The gold circles are proteins that only associate with Siglec-6. The blue circles are ones that associate only with Siglec-8, and then green are the ones that associate with both receptors. What you can see is really that, as I mentioned, Siglec-6 has a larger inhibitory footprint inside the cell. What's of particular interest here is that many of the genes that are unique to Siglec-6 are ones that regulate critical cell functions. In particular, we see several genes that are associated with cellular metabolism, energy production, energy regulation. And the data that we've generated to date indicates that these cells that are treated with AK006 seem to almost enter an anergic state and are not able to be activated. And we believe that that activity is really associated with these proteins that are involved in cellular metabolism. In addition, there are phosphatases that are activated uniquely by Siglec-6, and phosphatases, in general, can be thought of proteins that antagonize kinase activity. Okay, go to the next slide. Okay, so moving on to the drug side. We have two panels up here, one for AK002 and one for AK006. And we're comparing and contrasting the two antibodies. Both antibodies require Fc gamma receptor engagement of the antibody to activate the inhibition. So that, that's similar between the two drugs. Where they begin to differ is that when AK002 binds Siglec-8, it internalizes Siglec-8. So you lose the expression of the receptor to some degree. When you compare that to AK006, AK006 has a high residence time on the mast cells, which again, is associated with inhibition. So you effectively have a much higher antibody density on Siglec-6 than you do on Siglec-8, and we think that's also a key component to why six appears to be so much more potent than lirentelimab. And then again, lastly, six can induce ADCP, so we can reduce, in the right conditions, mast cell numbers, whereas mepolizumab does not have that functionality. Okay, so the next few slides will be data that supports what I just described. What you're looking at here are mast cells that have been activated through three distinct pathways, IgE, KIT, and MRGPRX2. And you can see in each of these cases, AK006 is significantly more potent than mepolizumab is on inhibiting mast cells. Okay. This slide shows the ADCP activity of AK006. In the middle panel, you're seeing the ability of AK006 to induce macrophage phagocytosis of mast cells, essentially at basically all doses. On the right side, what you're seeing is a comparison between AK002, AK006, and an isotype control. On the left side of that panel, you see mast cells that are incubated with resting macrophages, and in that setting, you do not see phagocytosis induced by AK006. When you activate the macrophages in the presence of AK006, you see the macrophages eat or phagocytose the mast cell, and you do not see that activity with either the isotype control or AK002. And that's really the right panel of that graph or that figure would represent what you'd expect to see in an inflammatory site in a condition like atopic dermatitis. Okay, so we've showed you some data comparing AK002 and AK006, and here we're putting AK002 and AK006 in the context of a positive control. So what we're looking at here are human mast cells that have been activated through the IgE receptor. And on the right side, you'll see the graph where you have AK002, has roughly 50% inhibition, and then AK006 and remibrutinib, which we're using as the positive control, both maximally inhibit mast cells in this particular assay. So again, 6 is more potent than 2 and comparably potent to remibrutinib in this assay. Right, so the next two slides will put AK006 in an in vivo context. And what you're looking at here is a model of anaphylaxis, and this is. This model was set up to essentially induce anaphylactic death in these mice. So on the left panel, what you're looking at is the change in body temperature, which is an indication that the animals are undergoing anaphylaxis. And on the right is a curve showing the survival. So in the case of AK006, only one animal out of seven died while on AK006, whereas 2/3 of the animals on placebo did. So what this shows you is, even when you're looking at a biological process, which is essentially at the limit, we're able to inhibit that process with AK006. And lastly, on the data slides, again, this is another in vivo experiment. And this one's interesting because this is a model where we establish inflammation, so this is a gut inflammation model. These animals, this is induced over the course of several weeks, and once the inflammation is established, we begin dosing AK006 for around a week or so, and then the animals are sacrificed, and we examine the gut inflammation. And what you see on the left panels are a sham control. Essentially think of that as baseline. You have the isotype control for Siglec-6, and then you have the Siglec-6 panel. And what's clear here is that six, even after established inflammation, six is able to reduce mast cell numbers back to baseline. When we phenotype those mast cells, they also have a resting phenotype, and that's measured by CD63 expression, and sixty-three expression's really a measure of mast cell degranulation. So you can see that the mast cells are back to a baseline phenotype as measured by CD63. Additionally, we did some transcriptional profiling on those mast cells in the gut, and the first row there is the baseline transcriptome, and then you see the next row is isotype control, and then lastly, Siglec-6. What's really interesting here is even at the transcriptional level, you see in the presence of Siglec-6, the mast cells looking more like baseline mast cells. And this is a finding we see across the different model systems we use, whether they're our murine models or our human ex vivo work. This result is consistent. Okay, so in terms of our Phase 1 program, this is a comprehensive Phase 1 program. It includes a single ascending-dose arm and a multiple ascending-dose arm. These are randomized, double-blind, placebo-controlled cohorts. In SAD, we'll be looking at five different doses listed up there. In the MAD study, we'll be looking at three different doses. There will also be a subcutaneous cohort, in the next few weeks or so, we will begin dosing our subcutaneous formulation of AK006, that's right on the heels of the IV formulation. Then lastly, there'll be a cohort of spontaneous, Chronic Spontaneous Urticaria patients. This also will be a randomized, double-blind, placebo-controlled study. These patients will have the same characteristics, or we'll use the same criteria we just used in our Phase 2 study, to enroll these patients. They will be given four monthly doses of the IV formulation of AK006. In terms of the endpoints across the Phase 1 study and the SAD and MAD cohort, we will be looking at safety and tolerability, PK/PD. In addition, we have taken skin biopsies from the SAD cohort, and we will also within the MAD cohort, and that'll allow us to look at target engagement and occupancy. And then we will also, of course, have the subcutaneous bioavailability data. In terms of what we're looking at in the CSU study, it again will be the same set of endpoints we're looking at from our Phase 2 study. We'll look at change from baseline and UAS7, as well as some of the other endpoints that Craig described earlier. Okay, in terms of where we are currently, we have completed the SAD dosing, and we're collecting all that data and analyzing it currently. The MAD cohort has also been initiated. The CSU study is on track to begin in early Q1, so everything looks good there, and we expect to start that study per guidance. In the next few weeks, we will initiate the subcutaneous study, so that also is on track and looking good. And then we also have budgeted for one additional therapeutic indication. When we finalize that information, we'll make it available to everybody. The goal there is to start that indication sometime coming out of the summer. And then for illustrative purposes, we put a Phase 2 study in there to show if we have positive data in CSU or an additional indication, we can very quickly go into a Phase 2 study. Right. In terms of the upcoming milestones, we have them listed here. In Q1, we will complete SAD and MAD dosing with the IV formulation. We will initiate our subcutaneous cohort. We will report the SAD and MAD safety, PK, and PD, as well as the Siglec-6 receptor occupancy from the skin biopsies in those patients. And that'll be an important data point because it will... It obviously will demonstrate that we're getting target on drug on target, and then we'll be able to correlate that with our activity from our preclinical models. In the second quarter, we will also initiate the CSU study. In the third quarter, we will report the results from the sub-Q program. Primarily there, we're looking at bioavailability, but we'll also have the same data we generated from the SAD and MAD IV cohorts. By year-end, we anticipate having the top-line data for the CSU cohort. That concludes our prepared comments, so we can move into Q&A. Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from Sam Slutsky with Life Sci Capital. Your line is now open. Hey, thanks for the questions. Everyone, a couple for me. I guess first, given that you've presented the same type of kind of preclinical experiments with AK006 and lirentelimab on mast cell inhibition, and given that these experiments did show some mast cell effect with lirentelimab, I guess, how do we get conviction on the preclinical inhibitory findings with AK006, prior to clinical data? And then anything that we could potentially conclude from the skin biopsies from healthy volunteers? Yeah. Thanks, Sam. Yeah, I understand. I mean, we're, you know, the desire to want to have lirentelimab read on AK006, we understand that. I think the key thing to realize here is that Siglec, the AK006 program was developed from its inception to be a potent mast cell inhibitor, and that those antibodies were optimized to be potent mast cell inhibitors. You know, historically, lirentelimab was developed to be a mast cell depleter. And because it was also expressed on mast cells, we had some amount of mast cell inhibition. You know, now that we have the answer, it's easy to look back and say it wasn't enough. But in terms of six, six is more potent than lirentelimab in every single assay we've developed, and over time, we've developed more sophisticated assays demonstrating that inhibition. And that not only is in mice, but also in human ex vivo tissue. The other, I think, key data there is that. We now have a positive control we can look at with human clinical data in remibrutinib, and AK006 appears, you know, at least as potent as remibrutinib in mast cell inhibitory assays, and it could be more potent because of the ability of the molecule to inhibit a broader set of activating receptors. So I think those are the things that give us confidence about six being more potent than eight. In terms of the biopsies, you know, we will have. The goal of those biopsies is to look at occupancy. And, you know, we have now a larger data set in animals showing the amount of occupancy that leads to inhibition. And with that data, with the human data, we can start drawing parallels to the animal data. Additionally, we will be looking at activation in those biopsies. So the hope is that we'll be able to demonstrate mast cell inhibition in those mast cells from those biopsies. And, you know, we're optimistic that will happen given what we're seeing in the animals, but we'll have to wait until we get that data, and once we get that, we'll share it with you guys. Okay. And then maybe I missed it, but in terms of sharing that data, I guess, what kind of format and so forth are you expecting? Well, well, I guess it depends when we finally, you know, when we have it compiled and it's ready to go. I hope it's sooner rather than later, but, you know, if we're at a investor conference and we have the data, we'll certainly share it there. If it makes more sense to do a analyst day or something similar, we'll share it in that venue, to make sure that we get the data out there and everybody understands, you know, what it means and what we believe it means. Got it. All right. Thanks. Yep. Thanks, Sam. Please stand by for the next question. Our next question comes from Joseph Thome with TD Cowen. Your line is open. Hi there. Good morning, and thank you for taking my questions. Maybe just as it relates to the AK006 mechanism, will you be able to see a reduction in serum tryptase in the healthy volunteer studies? And, do you expect to show that, maybe why or, or why not? And then if you were to look forward to a Phase two in CSU, hopefully for AK006, is there anything about the Phase two in lirentelimab that you learned that you would alter the Phase two trial design, either in terms of, you know, sites, patient enrollment, endpoints, anything that you would like to change, I guess, in a future trial? Thank you. Sure. Yeah, thanks for the question. So taking the last question first, you know, looking for silver linings in the trials, the trials were certainly well conducted. You know, placebo rates were very good, so had the drug been active, you know, there would have been no problem to show that, to show a delta there. So we weren't fighting with placebo. So I think, you know, how the study was conducted and how those patients were enrolled, there might be minor tweaks, but nothing major. And then your other question was around serum tryptase. I would not expect total tryptase to go down because the mast cell killing part of AK006 is localized to an inflammatory setting where they're activated macrophages. It's not a pan mast cell killer. What we could see, and, is that in the biopsies... You know, the important part of tryptase is active tryptase. So in terms of a mast cell being activated and what it's doing in a local inflammatory environment, it's really the active tryptase that's relevant. Total tryptase is really a marker for mast cell burden. So it's possible that we could see a change in active tryptase, and we'll certainly look at that. Great. Thank you very much. Sure. Please stand by for the next question. The next question comes from Yasmeen Rahimi with Piper Sandler. Your line is open. Good morning, team. I'm sorry about this disappointing readout, but, you know, appreciate all the color and the transparency across all the programs. I guess, I wanna kind of go back to the question that, you know, had starting off the call, the investors sitting here and thinking, I think even going into this data, there was a lot of enthusiasm around AK006. And the question now is, am I gonna get POC data on the heels of the MAD to give me conviction based on PD biomarkers to success in CSU as well as potentially within other indications? So I guess I know it's early to set expectations, but simply said, do you think we're gonna get a concrete answer post the MAD readout on the utility of this product? And two, how do we connect PD biomarker data to actual treatment responses in CSU? Really, really appreciate that, because that's what it comes down to. It's like, you know, if that answer could be there, then I think that could be very helpful for a lot of the listeners on the call. Yeah, thanks for the question. We completely agree, you know, with what you're saying there. You're breaking up a little bit, so I think I got the- Oh. Gist of... Sorry, it was a bad connection, but I think I got the gist of the question, which was, when we look at the SAD and MAD biopsy data, what information... The information that we get from that, how will that convince or not people that we have activity on Yeah on the mast cell, and how that would translate to a CSU indication? Did I get that? That's correct. Okay. Great. Yeah, so, yeah. So I think the model system we've been using relatively recently is something we call our FIMS model. It's a mouse model that essentially is mimicking what kind of a healthy volunteer. So it's kind of a healthy volunteer mouse, so to speak. And what we know from those studies is that when you give a single dose of AK006 at a concentration that leads to the appropriate amount of receptor occupancy, that you see essentially those mast cells are shut off, and you're not able to activate them. And we showed some of that data and then characterized what's going on inside the cell. We've done similar experiments with human cells ex vivo and seen similar results. So our hope is, in the healthy volunteer study, and given the mouse data, I think we're, you know, we're increasingly optimistic that we could see a PD effect on the human biopsy samples. And so first and foremost, we wanna make sure that the antibodies get into the target. And I, you know, think that's one that I'm probably the least concerned about. There's no reason why the antibody shouldn't get there. And given the high residence time, it'll get there and stay there. So I think we'll be... You know, that'll be important, but I'm pretty confident that we'll see that. Then the next question we'll try to ask and answer is, if we take those mast cells that have been treated with AK006, you know, or placebo, and we activate them through the IgE receptor, do we see inhibition? And, and what's also embedded in that model, which I think if that data is positive and mimics what we saw in our murine model, we are not cross-linking the Siglec-6 molecule. So whatever inhibitory activity has happened to those cells has happened in vivo, and then we stimulate those mast cells in vitro with a non-cross-linking antibody that activates the IgE receptor. And so if we can show inhibition there in quote, "healthy human tissue," I think that bodes very well for our ability to inhibit a mast cell in an urticarial lesion. Do you guys have any other? Yeah, so did that get to the question? Yeah, no, that's helpful. That's very helpful. And we know you're in a tough situation, giving as much clarity on bar for success and when the next steps are. So we appreciate all your comments you're making and helping us through this process. Sure. Thanks. And, you know, I guess the good news is we'll have the data relatively soon. So, you know, we'll have- Yeah. the SAD data, and then we'll have the urticaria data by year-end. So, there's not that long to wait. Yeah, so. Yeah. Thanks, yeah. Thanks. I'll jump back in the queue. Appreciate all the comments. Please stand by for the next question. The next question comes from Tim Lugo with William Blair. Your line is open. Hi, team, this is John on for Tim. Thanks so much for taking our question. I was wondering if you could talk a little bit more about the additional preclinical studies that you're planning. Are those more focused on additional data to support AK006 and CSU, or are they on, uh, indication expansions, or should we expect an update on a new candidate? Well, I would say the bulk of the work that's being done in research is in support of AK006, elucidating the mechanism, and processing the clinical samples that are coming in. So that's a lot of work that group's doing. There are also programs that, you know, we continue to push forward there, and those are, you know, those are relatively low burn, but we've talked about those in our presentations briefly before. So that is still ongoing. But you know, the burn on that, you know, today or yesterday is very low, so there's really no change there. So the work primarily centers around AK006. All right. Thanks so much. Please stand by for the next question. The next question comes from Jonathan Wolleben with JMP. Your line is open. Hi, this is Catherine on for John. I just have some quick questions. First one is whether you measured mast cell inhibition at all in the lirentelimab studies. If so, why not? And then if there's any read-through from those to AK006. And another question I had was why REM used the positive control? Does it... Yeah. So, when you're asking about lirentelimab, are you asking if we took biopsies, human biopsies and tried to look at the inhibition there? Is that, was that the question? Yes. No, we didn't. It's, I mean, it is, it's a bit of a tough thing to do in clinical studies. In the Phase 1 study, you have a little more control over it, but, in a Phase 2 study, that would've been somewhat difficult to have done. I, for better or worse, with lirentelimab, we had the open label data and the different forms of urticaria, ISM, and conjunctivitis, which indicated that the drug was active on mast cells, certainly above what you would expect to be a historic control. You know, as we've been talking about over the last year or so, it's, the big caveat is it's an open label study, so you never can be sure. But the short answer is no, we didn't try to get biopsies out of those clinical studies. And then the question of why Remy, you know, it's difficult, like with... I guess the question is why Remy versus an antibody or something like that? Yes. In the models, yeah. It, you know, you gotta, each of these model systems can be challenging to work with, and because of the different MOAs of the antibody, your ability to get the antibody, whether it will work in an animal model or in a human ex vivo system, those are all challenging and can take a lot of time to optimize. With a small molecule, it's relatively simpler to do that. And at the time these data were generated, there was availability of human clinical data showing that Remy worked, so it was just a convenient way to demonstrate comparability between AK006 and a known drug signaling through a known pathway that's relevant in an indication that we're interested in, which is CSU. So that was really the rationale there. It just takes, it's a, there's a lot of complexity to comparing the antibodies together. That makes sense. Thank you so much. Sure. Please stand by for the next question. The next question comes from Paul Choi with Goldman Sachs. Your line is open. Hi, thank you. Good morning, everyone, and thanks for taking our questions. With regard to the data timeline for the Phase 1 data of the IV AK006 version by year-end in the CSU patients, can you maybe just comment on, you know, how you think about additional development of the formulation there and just kind of what the status is of sub-Q AK006, just as you think about the eventual and future product presentation for AK006, and just sort of what timelines might be there? And then I had a follow-up question. Sure. Happy to, Paul. So, the sub-Q formulation is kind of right behind the IV formulation. So, we should have the information around sub-Q, well, can you go to the timeline? I just wanna make sure I got the timing right. It'll be kind of Q3 when we'll have the information we need to know how sub-Q compares to IV. And then we'll have the benefit of having all the SAD and MAD data from IV. So we'll be able to look at target engagement, and PK. And so those are really the pieces that we need to then go into a clinical study with sub-Q. The plan is to use the IV for urticaria, and unlike lirentelimab, there, because it does not induce ADCC, you don't tend to have IRRs, and so the drug can be delivered much more quickly than we did with lirentelimab. So that's a nice advantage of the drug as well. And then, for an additional indication, we would have material ready to go, sub-Q material ready to go in the late summer for those studies or fall. So it's really right behind it. Okay, great. So just to clarify, the POC will just strictly be for the IV version, and then all subsequent development would be sub-Q, more or less, in the clinic in 2025. Is that correct? That, that's the operating assumption, yeah. You know, assuming that the sub-Q looks good, when we have no reason, you know, the formulation appears to be, you know, very good. We're able to concentrate it. It's not viscous, stable, so everything seems to be good there. So, you know, knock on wood, we'll get no surprises there, and then that would be the plan, would be to take the sub-Q into any subsequent clinical indication. Okay, great. And then as a follow-up question, as you're thinking about the CSU development, with the sub-Q in 2025, how are you thinking about the evolving treatment landscape? You know, Regeneron did have a bit of a setback there, but, you know, they'll presumably be on the market at some point. And so as you're thinking about trials and patients, you know, both in terms of that drug and maybe other drugs, are you thinking about maybe evolving your clinical trial design versus what, you know, strategy versus what you did here with lirentelimab? Short answer is no, but if you have, like, is there a specific, do you have something specific in mind? You know, we'd be happy to try to address that. No, not any particular drug, but I guess just any, you know, particular learnings, I guess, as you think about your, Phase 2 results here and just sort of, you know, what maybe at, you know, first take, what you might think about doing differently as you think about trial design for, for 2025 for, for AK006? Yeah. Gotcha. No, I think, you know, we will, we will—our approach will be the same. You know, our view on the landscape, it, you know, it really hasn't changed since, you know, a few months ago. I think we, you know, we have the remibrutinib data now, we have the barzolvolimab data. I—you know, our view on that is unchanged, and our goal will be to have, you know, our hope is that we see efficacy on six that, you know, is somewhere comparable to barzolvolimab and certainly comparable to Xolair or better. And I think in that setting, we're in a very good situation because of, you know, what we would expect to be on a relative basis, a cleaner safety and tolerability profile. The other good news is we're going to be able to, if we do have positive data in CSU, we can rapidly move forward. So in terms of competition, you know, I guess in particular with KIT-targeting drugs, we're not that far behind there. I think with Dupie, you know, I think given its slow onset of action, I think Dupie probably falls into the bucket of, you know, if someone has asthma and urticaria, that's probably a pretty easy sell there. But I think in terms of making broad impact in the urticaria market, I'm not sure that it has the profile for that, but I certainly would never underestimate, you know, Regeneron there. And I think, you know, big picture, having more people in an emerging therapeutic area is a positive. That's in general our view, and that really hasn't changed. Okay. Thanks so much for taking our questions. Please stand by for the next question. The next question comes from Kevin Strang with Jefferies. Your line is open. Hi, good morning. Thanks for taking my questions. Just one more on the initial data for AK006 and healthy volunteers. Just more specifically, is there anything you'd say about whether there's a certain threshold for receptor occupancy that you're looking for in terms of correlating to your preclinical data? And then you mentioned internalization of the AK006 receptor. Is that something you can look at, too, and maybe compare to lirentelimab? Thanks. Yeah, I mean, generally, you know, we will try to find a dose that, you know, is close to saturated as we can get. And we're assuming that we're able to see inhibition from the human from the sad biopsies, you know, we'll be looking at the relationship to dose, to occupancy and to inhibition. So, based on what we've seen in animals, we, you know, we would want high occupancy, so we'll be going for as high as we can get. And, and, you know, that based on the animal data, we feel like we should be able to achieve that in humans. Sorry, I just blanked on the last part of the question. It was on the, internalization of the- Oh. the AK006. Yeah. Yeah. So, the internalization by six is significantly less. So when AK006 binds to Siglec-6, it effectively does not internalize very much at all. Whereas, you know, lirentelimab it does pretty quickly internalize, and, you know, that internalization had no impact on ADCC with 002, but I think it does probably have an effect on its ability to inhibit the mast cell. And I think that's why, you know, in addition to kind of the receptors being different, I think that's a likely explanation for why you see the minimal mast cell inhibition. In terms of like the relative amount, it is significantly different. Okay. Thank you. And then, just a follow-up on the ongoing trial. So anything you can say about the investigator enthusiasm or anything on the overlap in clinical sites or investigators for the AK006 studies versus the MAVERICK study? Thanks. Yeah, I mean, there were, you know, there was enthusiasm for lirentelimab. You know, we got those studies essentially enrolled in around a year, so those, and they were relatively large, so that wasn't a real issue. For the AK006, we are using a subset of the MAVERICK trial site. So, just selecting the, you know, we don't need quite as many, so there's a subset of those studies for those centers that we're using. And, there seems to be a lot of enthusiasm around six. You know, since we introduced it, I think between investors and investigators, given the kind of the biology associated with targeting Siglec-6 has generated a lot of interest. And those folks are enthusiastic, and we're well down the road to having, you know, those centers activated and ready to go right at the start of the second quarter. So all that's on track and looking really good. Great, thanks for taking my questions. Please stand by for the next question. The next question comes from Jennifer Kim with Cantor Fitzgerald. Your line is open. Hey, thanks for taking my questions. My first question is, I'm not sure if you specified, but when can we get more clarity on the, I guess, specifically, what level of detail will be included in the second half or the second quarter healthy volunteer data, including whether or not you're going to include data measuring active tryptase? And then a similar question in the third quarter sub-Q data. What are you thinking of a top line, or are you thinking of more detailed presentation at venue? Thanks. Yeah. So what we're doing in the SAD, MAD, and the sub-Q study is, we're taking baseline biopsies. We are also taking biopsies after different time intervals post-dosing. And we're looking at, then we stimulate the cells through the IgE receptor and determine whether we can inhibit it based on CD63 expression. And we'll also look at the supernatants from those experiments to see if, you know, if there's a change in CD63 expression, that should also correlate with a change in the secretion of inflammatory mediators. So that's the type of data that we will hope to present. These are difficult experiments, so we're collecting the information. When we get it, we'll make sure we update the market really one way or the other, so everybody has the information. Sorry, I can't remember sub-Q. sub-Q is the same. It's exactly the same experiment. So we'll... And, you know, assuming you reach the same blood levels, there shouldn't be any difference in the sub-Q versus the IV. Okay, and is there somewhat of a limited read-through that investors can make from the second quarter readout? Can you level set in terms of what you're hoping to show in the Phase 1 IV data in CSU, and how soon after could we then see data up in the sub-Q cohort? Thanks. Well, I think- Oh, in non-healthy volunteers. Sorry. So, you're asking what, what can we, what can investors, draw from the healthy volunteer biopsy data? Yeah, sort of level set what you're hoping to show in the Phase 1 IV data before the end of the year in the CSU cohort, and then could you just walk through when we could see data beyond healthy volunteers in a with the sub-Q? Well, we'll have the Chronic Spontaneous Urticaria study is set to initiate in early Q2. That study, as we've mentioned, I didn't mention it today on the call, but we've talked about this previously, is going to be around 30 patients with twenty on active, ten on placebo. And it'll be a single dose level that we'll determine from our SAD and MAD studies. That's, you know, if the data is positive, it should be very compelling because it's a relatively large proof of concept study that's randomized, double blind, placebo controlled, and it's testing the registrational endpoint. So that study, you know, we would hope it would be statistically significant, but similar to what other sponsors have done, it should be clearly numerically different, and that's what we would hope to see. And I think if that does turn out to be true, and it's competitive with others, that is a, you know, a huge milestone and value-creating milestone. In terms of how quickly after that we could start sub-Q, it would be reasonably quick. So if we have top line data, we have sub-Q's ready to go. We will have the information on the bioavailability, so we'll be able to match PK. And then we would initiate a Phase 2 study as quickly as we can after that, which practically is probably, you know, six months or so to get everything going. And so it would happen pretty quickly. We have the material manufactured, so all of that is in place to move rapidly, which is why I mentioned that, you know, we're not that far behind competitors with AK006 and urticaria. And, may I, if I could squeeze in one more question. The budgeting you've made for an additional indication, is that decision ahead of the CSU data and specifically, so that indication would be outside of CSU, right? Yeah, that would be outside of CSU. Okay, and it would come ahead of the CSU data? No, but from a practical standpoint, that would be after. So that's the goal there would be to try to get that data by mid-2025 to end of 2025. But it does... What's partially baked into that is the expectation that CSU would be positive. Okay. All right, thanks. Please stand by for our last question. Our last question comes from Thomas Smith with Leerink Partners. Your line is open. Hey, guys. Good morning. Thanks for taking the questions. For AK006, obviously, there will be a lot of important learnings from the healthy volunteer experience, but could you expand a little bit on how you're thinking about your ideal product profile for CSU? It sounds like you're initially looking at monthly dosing intervals, but is there a potential to get to less frequent dosing here with more data? And then, relative to Xolair or Dupixent, are you open to differentiate here more on efficacy or safety or convenience or sort of all the above? Yeah. Yeah, thanks for the question. Yeah, so certainly, based on what we've seen in the animal models, it does appear that in following a single dose, you do have kind of profound inhibition of the mast cell. That's something we'll just have to figure out empirically in humans. And so, certainly with positive, you know, data in urticaria, the next study would be a dose range and probably dose schedule study to see how long the inhibition lasts. But, depending on the PK and given what we've seen in animals, it's reasonable to assume if the drug is there on target, it's going to inhibit. So it really comes down, partially to a PK argument, but then also it does appear that these changes that are made to the mast cell do extend past a PK, past the when you would expect you'd start losing binding on the receptor. But yeah, in terms of our profile, if we got longer duration dose, that'd be great. I think monthly sub-Q is fine, and competitive, especially between Dupixent and Xolair. I guess Xolair's given monthly or less in urticaria, up to twice a month in asthma, and Dupixent's twice a month. We would be looking for a profile that would be comparable to what you've seen with the KIT inhibitor, barzolvolimab, so without the safety and liability or tolerability liabilities. That would be what we'd be going after. Yeah, I don't know if you guys have anything else to add to that? No, I think that, I think much like you know, the comments around the competitive landscape, you know, our view hasn't really changed. And so, you know, a product that has a you know, a good safety profile with efficacy similar to Xolair could be successful. And obviously, as the efficacy for you know, increases, that profile becomes you know, more, even more attractive. So obviously we'll be aiming high, but I think that's probably the minimum product profile we'd be looking for. Got it. That's helpful. Thanks for taking the questions, guys. Sure. Thanks. I would now like to turn the call back to Robert for closing remarks. Well, we'd just like to thank everybody for their attention and questions. You know, it's a tough day, but we are, you know, available if there are any additional questions that you might have. So, please reach out, and, and again, thank you for participating in the call. This concludes today's conference call. Thank you for participating. You may now disconnect.