Greetings, and welcome to the Allakos Investor Day. At this time, all participants are in listen-only mode. A question-and-answer session will follow the formal presentation. As a reminder, this conference is being recorded. I'll now turn the conference over to Mr. Robert Alexander, CEO. Mr. Alexander, you may now begin your presentation. All right. Thank you. Good morning, everyone, and thank you for joining the call. Before we begin, a reminder that we will be making forward-looking statements, so please refer to our filings with the SEC. With me here today are Craig Paterson, our Chief Medical Officer, Baird Radford, our CFO, Brad Youngblood, our Head of Research, and Adam Tomasi, our President and COO. As for the agenda, following my introductory remarks, Craig will go through our KRYPTOS and ENIGMA studies. We'll then be joined by Dr. Evan Dellon to give his perspective on the EGID space and specifically these two clinical studies. I will then go through the scientific rationale for our programs with lirentelimab and atopic dermatitis in chronic spontaneous urticaria. Following that segment, Dr. Maurer will join us to give his perspective on chronic urticaria and specifically, CSU as well as, lirentelimab in that indication. Brad will then give a pipeline update and introduce a new molecule we have in development. We will finish with a financial update and go to Q&A. Before I hand it over to Craig, I'd like to frame our presentation today. I think everybody knows we received surprising results from our studies toward the end of last year, where we met the histologic endpoint, so we had complete ablation of eosinophils in these populations, but we missed the symptomatic endpoint. We spent the intervening weeks analyzing the data, discussing it with our KOLs, to determine what, if anything, went wrong to really dig into the data and figure out what happened. What became clear was that we inadvertently enrolled patients with mild disease in both studies. This led to a significant amount of variability or noise in the study population. We then analyzed the data in patients, which was a significant number of the patients in these studies that had the correct demographics, which are moderate to severe patients that are biologic indicated. A clear signal emerged with drug over placebo. Then we had clear evidence of activity on the symptomatic endpoint to go along with the clear evidence of activity on the histologic endpoint. With that, I'll turn it over to Craig so he can run through the data in more detail. Thank you, Robert, and good morning. I'm gonna now provide more detail on our KRYPTOS study, which was a phase II/III study in eosinophilic esophagitis, as well as our phase III ENIGMA 2 study, which was in patients with eosinophilic gastritis and/or eosinophilic duodenitis. Starting with our phase II/III study in eosinophilic esophagitis, you'll remember that this was a multicenter randomized double-blind placebo-controlled trial in patients with active moderate to severe symptoms and biopsy-confirmed eosinophilic esophagitis. We randomized about 276 patients evenly between a high dose of lirentelimab, low dose of lirentelimab, and placebo, and subjects received six monthly doses. In keeping with FDA guidance, we also included adolescents aged 12- 17 years of age and also had an open-label extension available to study participants. In terms of endpoints, once again, we constructed this study very much consistent with the current FDA guidance with co-primary endpoints. The first co-primary endpoint was a histologic responder definition, and this was the proportion of patients achieving less than or equal to six eosinophils in a peak high-power field. We also had a symptomatic co-primary endpoint, and we used the Dysphagia Symptom Questionnaire or DSQ. Other endpoints included a percent change in DSQ from baseline, activity in adolescents, as well as activity in our open- label extension. Moving on to the data. This is the histologic co-primary endpoint, which once again was the proportion of subjects achieving the eosinophil response in the tissues. On the left, you can see the primary analysis, which was our intent-to-treat analysis. Both the high dose and the low dose lirentelimab dose arms achieved a very robust and significant response in terms of proportion of patients achieving that response. On the right, you can see the analysis with observed data. This is really restricting the analysis now to patients that had tissue biopsies that were evaluable for histology. Once again, you can see that we really crushed the eosinophils in the tissue, both on the high dose and the low dose as compared to placebo. Moving to the symptomatic co-primary endpoint. Looking at a further definition of histologic response, we also looked at the proportion of patients achieving a tissue eosinophil less than or equal to one. In keeping with the mechanism of action of lirentelimab, we expected that we could really achieve a more normal level of tissue eosinophils. Indeed, that was the case with about 95%-96% of those on high dose and low dose achieving that threshold. Moving now to the symptom co-primary endpoint. This was the change in DSQ, and this is the analysis that caught us by surprise. On the left, you can see the absolute change in DSQ from baseline and neither the high dose or the low dose separated from placebo. As we looked at the percent change, we saw some suggestion of activity at the high dose and nothing at the low dose as opposed to placebo. As we looked at this, we really began to try to understand what happened with our data in terms of the symptomatic responders. As always, a good place to start is to go back and check randomization, as well as look into details of the patients that we enrolled in our study. With that in mind, I'm showing you here the baseline demographics and patient characteristics of the subjects enrolled in this trial. You can see the high dose on the left, low dose in the middle, and placebo on the right. Again, a number of the demographics and patient characteristics are shown. As we review this data both internally and with some of our key opinion leaders, including Dr. Dellon and Dr. Marc Rothenberg, we noticed a couple of trends emerging. First off, you'll see highlighted the duration of EoE, and note that several patients had a very short duration of disease. Likewise, we looked into therapies that were considered more standard of care, such as proton pump inhibitor use and topical steroids. We noted that these were lower than would be expected in this population. Likewise, if we look at the history of esophageal dilatations, we noted this was quite low. In fact, for the sake of reference, when we looked at the recent dupilumab study in eosinophilic esophagitis, we noted about a 43% history of esophageal dilatations. The reason that's important is with chronicity of disease, with the more moderate to severe reflux, patients tend to develop strictures over time. This was a suggestion that we might not have had the more moderate to severe patients, or that patients might not have had a sufficient duration of disease to be in this study. Likewise, as we look at the peak eosinophil counts in the tissues, we see a mean of around 60 eosinophils in a peak high-power field. Once again, to put that in contrast, the dupilumab study had just north of 80 eosinophils in a peak high-power field. We were slightly less eosinophilic than other studies of biologics in this disease. Interestingly, at the bottom, you'll note the baseline DSQ score, and this is very much consistent with what we've seen in other studies. As we walked through this, we were trying to find a way to better identify patients in this study that certainly would be candidates for a biologic therapy, but also identify subjects that might have been included that either had milder disease or maybe not even eosinophilic esophagitis at all. As we spoke to Doctors Dellon and Rothenberg, we went back through different ways that you can do this. Certainly, one is to look at the more proximal esophagus to see if there's still significant tissue eosinophilia at that level of esophagus, so to require it in two areas. The other was to set a higher threshold for the peak eosinophils. So one of the numbers that came out of the literature and in speaking with our KOLs was a number between 20 and 30 as a peak eosinophil count. In fact, the further we looked and the more we spoke with them, 24 seemed to emerge as a number that had been used in other studies and by other authors to help differentiate eosinophilic esophagitis from reflux. This is one of the references from a paper by Marc Rothenberg. What you can see basically is that less than 24 eosinophils in a peak high-power field can include people with other diagnoses, particularly when you're sampling the distal esophagus. Certainly reflux disease is one of those, and then allergy may come in on top of that. The suggestion is that if you really want to try to identify a population with primary eosinophilic esophagitis, you should look for those that have a peak eosinophil count of at least 24 in a single high-power field. Applying that number to our data and going back and looking at the baseline characteristics and demographics, we see the following. I'll start on the left, and you can see the population with those with a peak eosinophil count of less than or equal to 24. On the right now, you see the population with an eosinophil count of greater than 24. At first glance, it's pretty easy to see that these are very different populations indeed. Going back to the left side, where you have a count of less than 24, that accounted for about 17% of the patients in our study. Once again, if you look at the history of proton pump inhibitor use, the history of swallowed topical corticosteroids, and even esophageal dilatations, these are very low for this population, and certainly this number should be much, much higher. Likewise, looking at the tissue esophageal counts, you can see that these numbers are very, very low in general, and also the numbers in the more proximal or mid-esophagus are also very, very low. In fact, one of our KOLs commented that it's hard to tell if these patients had eosinophilic esophagitis or not, or would have better been treated with a proton pump inhibitor or other topical therapies. Likewise, if you look at the serum IgE levels, these are also very, very low for this or that would be typical of this population. As you're aware, eosinophils are important for mast cell activation in IgE. Looking now to the right side with the counts of greater than 24, you see this starts to become much more consistent with a typical EoE population with slightly higher use of both proton pump inhibitors and swallowed steroids. Tissue eosinophil levels now are more in keeping with what we've seen in other studies. Likewise, IgE, the mast cell activator, is also slightly more elevated. Now going back and using these cutoffs to look at our data, we see the following. On the left side, you see those with the eos count of less than or equal to 24. It's certainly obvious that we had a very, very large placebo response in those patients. It's very hard to distinguish any signal either from high dose or low dose when the placebo response is so robust. Now we set that filter to look at patients. There were 228 patients with the tissue eos peak above 24. We now start to see evidence of response, particularly at the higher dose arm. This is another way of looking at the same data. This time it's a% change from baseline. You can see again on the left for those less than or equal to 24 in a high-power field, we see a very large placebo response. Now on the right side, once again, you start to see activity, particularly in the high-dose arm for lirentelimab. Adolescents were another population of interest, and certainly they are to be included in studies of EoE as per the FDA guidance. It's also an interesting population because kids, before they're put onto a biologic therapy, are more likely to have exhausted all standard of care therapies or more conservative measures. I think most parents would agree that before you put your child onto a biologic therapy trial, you want to have exhausted all possibilities first. Going into this, we assumed that the demographics would support that. Indeed, as we look at the demographics in this population, that's exactly what we observed. In contrast to the adults or all the study population, you see a much higher use of proton pump inhibitors and swallowed topical corticosteroids. Likewise, tissue eosinophil counts are much, much higher. In fact, if you look at this population, it really looks like the overall population when you set that peak threshold greater than 24. Also looking at blood eosinophils, you can see they're much, much more elevated compared to the overall population. Likewise, serum IgE is much more elevated. Again, this is very typical for eosinophilic esophagitis. Looking at the response in this group of patients, we see that the eosinophil responders in the tissues really robust response both on the high dose and the low dose compared to placebo. We look at the change in DSQ from baseline on the left in terms of absolute change. We see the high dose and low dose both numerically outperforming placebo. We see it as a percent change, and once again, a very, very similar pattern. What's interesting in this population is now we see evidence of both activity in both the high dose and the low dose. Certainly it draws to mind that maybe we're having activity now on the mast cells given their high IgE levels in general. In terms of safety, for the overall study, we really saw no new safety signals when compared to the ENIGMA study in the phase II population and also any other lirentelimab studies to date. In terms of treatment- emergent adverse events occurring in at least 5% of the patients, the most common was infusion-related reaction followed by headache. In terms of serious adverse events that were deemed possibly drug-related, we saw three in total on this study. Two were on patients on the high dose of lirentelimab arm. Both of those occurred with the first dose and were infusion-related reactions, which were easily managed and transient. O ne of these was on placebo. This was an episode of angioedema in a patient with a history of angioedema, and this occurred on the fifth dose. Overall, the safety profile was very consistent with what we've seen previously, and lirentelimab was well tolerated in this study. Moving on to the open-label extension phase of the study. I'll direct your attention to the panel on the left, and that is the absolute change from baseline. On the far portion of that panel in the solid bars, you see placebo in the dark gray, low dose in the light blue, and high dose in the dark blue. Over to the right of that, now you see the hashed bars, which represent what happens to each of those groups once they enter the open-label extension. With placebo, we see a nice response now as they switch over to lirentelimab. With the low dose, we see a continued improvement. Likewise, with the high dose, we see that ongoing and deepening improvement, suggesting evidence of durability. On the right is the same data now just expressed as a percent change from baseline rather than absolute change, and we very much see the same effects. Overall, as Robert mentioned, we had a phase II/III study that included patients, some of whom we believe may not have truly had a diagnosis of eosinophilic esophagitis or whose diagnosis was considered more mild and would not have been appropriate for a biologic therapy. We saw a clear activity though in those with more moderate to severe eosinophilic esophagitis and also clear evidence of activity in the adolescent population. We observed durability of effect in the interim analysis of our open-label extension. As mentioned, it was well tolerated in both adults and adolescents with eosinophilic esophagitis. I'm now going to move to our phase III ENIGMA 2 study, which was in eosinophilic gastritis and/or eosinophilic duodenitis. Once again, this was a multicenter randomized double-blind placebo-controlled trial in patients with moderate to severe symptoms and biopsy-confirmed EG and/or EoD. We enrolled 180 patients, and they were evenly randomized between lirentelimab and placebo for six monthly doses. Also again, we offered an open-label extension. Consistent with EoE, we had co-primary endpoints, the first being histologic, and the responder definitions are shown here. We also had a symptomatic co-primary endpoint, which was the absolute change in their patient-reported outcome of Total Symptom Score- 6. Other endpoints included percent change in TSS-6 from baseline and also a proportional responder analysis looking at patients that achieved at least a 50% and at least a 70% improvement in TSS-6 from baseline. This is showing the histologic co-primary endpoint, and again, really nothing different than what I showed you with our eosinophilic esophagitis. On the left is the primary analysis, which was the intent to treat analysis, and we have a very high proportion of patients achieving histologic responder status at week 24 compared to placebo. On the right, you can see the observed data, which is only those patients with tissue that had evaluated histology. Once again, you can see a very high proportion of patients achieving the histologic responder definitions. Moving on to symptoms. This is again where we were surprised. We really saw no separation on the absolute change from baseline in TSS-6 between active and placebo, whether we looked at that as an absolute change from baseline or a percent change from baseline. This was the pre-specified secondary endpoint with the responder threshold analysis. As I mentioned, the responder thresholds we predefined were 50% and at least a 70% reduction. Shown here for completeness and clarity, I've also included a 30% reduction and a 90% reduction. This was interesting because at the 30% reduction levels are greater than equal to 30%, it was really hard to differentiate any signal from lirentelimab, given the very high placebo response rate. As we raised that bar further to 50%, 70%, and 90%, we now started to see activity in favor of lirentelimab. Once again, trying to understand this output, we went back and looked at the baseline characteristics and demographics. Also because we had a very successful phase II study that was published in The New England Journal, we had a chance to go back and compare it to what we had observed in terms of the population that was enrolled in our phase II study. Those comparisons are shown here. On the left side, we have our phase II ENIGMA study labeled as E1, and there were 65 patients in that study. To the right of that, you see our phase III ENIGMA 2 study, which is the one we're speaking about today. You can see the active group in the middle, followed by placebo on the far right. I've highlighted just a few things that I wanted to draw your attention to in terms of comparing these two study populations. One is a history of EG and/or EoD. That was about 80% of the subjects that came into our phase II ENIGMA study. When you look at the phase III study now, it's about 30%. Likewise, for a history of irritable bowel syndrome, it was very low in the phase II study and somewhat higher at around 38% or 39% overall in the phase III study. Likewise, as we look at the tissue eosinophil levels, you can see they were considerably higher in the phase II study compared to the phase III, and that same trend held true for the blood eosinophils as well as the serum IgE level. Baseline Total Symptom Scores, however, were very similar across the groups and between studies. One of the common threads that made an interesting comparison in this particular study was the fact that we included sites from our original phase II ENIGMA study in the phase III program. This gave us an opportunity to say that the patients that came from these sites somehow demographically or characteristically look the same or different than what we observed or saw in the phase II program. I have that analysis for you here. Once again, on the far left you see the phase II ENIGMA study and the demographics and characteristics of those patients. In the middle now you see the same ENIGMA sites that were included in the phase III program. Then you see on the far right now new sites. This was a study of about 180 patients. Of course, we had to expand into newer centers beyond those that we had included in our original ENIGMA study to enroll 180 patients. As we look at this, we can see again differences between the ENIGMA sites that participated in the phase II program and the same sites that participated in the phase III program. As you look through this, you'll see that the patients that came from the ENIGMA sites in the phase III program looked a lot more similar to those that came from the phase II study. Those from the newer centers in general looked a fair bit different from the newer sites that participated in ENIGMA. N ow just going back to reference of how patients performed in the phase II program shown on the left, this was the mean change in TSS-6 from baseline, p hase II program. Now as we look at the patients that came from the ENIGMA centers that participated in the phase III, you can see a very, very similar response. Likewise, the responder threshold analysis that I showed you previously, we applied that to the data from the phase II study, and that's shown on the left. You can see a very nice response for lirentelimab at 30% all the way through 90% reduction in TSS-6 score. If you look at the patients that came from the ENIGMA centers in the phase III program, you again see a very, very similar response rate and similar pattern. In contrast, we looked at the patients that came from newer centers, so the non-ENIGMA centers in the phase III program. We really saw no response or no separation between active and placebo. Likewise, applying the same responder threshold analysis, once again we see a very large placebo response at around a 30% reduction level. This time, as we raise that threshold higher through 50%, 70%, and 90%, we still really see no meaningful separation of active from placebo in those patients. Moving on to safety. Once again, I'm showing you the treatment-emergent adverse events that occurred in at least 5% of the patients. Once again, the most common treatment-emergent adverse event was an infusion-related reaction, followed by fatigue. We saw no drug-related serious adverse events in this study. Once again, the safety profile was very much consistent with what we reported out in the phase II ENIGMA study and other lirentelimab programs to date. For the open-label extension, I'll show you once again the absolute change in TSS-6 from baseline on the left side. Just to orient you again, weeks 23 and 24 in the black and darker blue are the last two weeks of the double-blind randomized placebo-controlled phase. For reference, as you move to the right of that now, you can see how those patients performed at weeks 45 and 46 in the open-label extension. Once again, you see a nice response of those that were on placebo initially and that transitioned over to open-label extension AK002, and likewise, evidence of durability and ongoing deepening response for those that had been on drug, and now remained on drug during the open-label extension. On the right, I'm showing you the same data, this time just expressed as a percent change from baseline. To summarize, when we looked at the patients that came from the sites that participated in the phase II ENIGMA study, we really were essentially able to reproduce the original study results. As we look through the patient characteristics, and this really is about patient characteristics more than we believe the sites, we looked at those patients. In general, they had higher tissue eosinophil counts as well as higher peripheral blood eosinophil counts, and as I mentioned, higher IgE levels. We saw evidence of durability of effect in our interim analysis of the open-label extension. Once again, lirentelimab was well tolerated in patients with EG and/or EoD. I'm now briefly gonna speak about our EoD or eosinophilic duodenitis-only study, and this is a phase III program. Once again, a multicenter randomized double-blind controlled trial in patients with EoD only, active moderate to severe symptoms, and biopsy-confirmed EoD. One of the pieces of this study that is also of interest is that we are also evaluating the distal small bowel as well as the colon. Subjects included in this study also have a colonoscopy with biopsies from the terminal ileum and various segments of the colon and rectum to better characterize the eosinophilic disease in these regions of the GI tract. This was 93 patients split evenly between two arms, lirentelimab and placebo for six monthly doses. Consistent with the AK002-016 study, we have co-primary endpoints, both histologic as shown here, as well as symptomatic, which was the absolute change in the TSS-6, as well as a number of other secondary endpoints, including percent change in the tissue eosinophil counts, a responder analysis, so the patients who achieve eosinophil thresholds and at least a 30% improvement in TSS. We're gonna explore changes in colonic eosinophil counts as well. This study was fully enrolled as of December of this past year, and we anticipate it will complete in the mid-portion of this year. Looking at the baseline demographics and characteristics, we realize that this population is more similar to what we've seen in our ENIGMA 2, meaning they're a slightly milder population. We anticipate the results will be very similar, likely to what we've just shown you for the ENIGMA 2 study. We will use this data to inform our correspondence with the FDA. Next steps, we are excited along with our KOLs of the data that we showed you in the eosinophilic esophagitis, and we believe we have strong enough data to approach the FDA in an end-of-phase II meeting with this, and we'll update the market accordingly following this meeting. In terms of EG and/or EoD, as I mentioned, we're gonna await the outcome and the data readout of our AK002-021 EoD-only study, and we'll incorporate that data into the analysis of the ENIGMA 2 study. We will meet with the FDA once that data has been fully analyzed to discuss the steps forward. With that, I'm gonna turn it over to Professor Evan Dellon. He is a Professor of Medicine, Gastroenterology, and Epidemiology, and Director for the Center for Esophageal Diseases and Swallowing at the University of North Carolina School of Medicine. Dr. Dellon. Hey, thank you so much. It's a pleasure to be here and talk. I think, you know, in looking at these data, I really had the same response probably as everybody with the top-line data. You know, seeing the impressive histologic responses, and then seeing that the symptom data did not meet the co-primary endpoint, and of course, being disappointed with that. I think there was a few things, even just with the top-line data, that I wanted to convey. That's, you know, first, the medicine mechanistically, of course, was working, you know, it, the way we expected. The symptoms were improving. You know, they were improving in the active arm. The problem was, of course, that they did not improve, or they improved in the placebo arm. This is actually not new to the field of EoE. This has been seen multiple times in prior studies, not only of, you know, biologics, but actually in topical steroids as well, and not just in the U.S., but in other studies around the world. It comes down to, in general for these studies, patient selection. For the previous studies, where this was seen, you know, both with esophageal-specific formulations of topical steroids and with other biologics, there were a lot of lessons learned about the correct patients to enroll in the studies, the way to assess symptoms, and the way to think about outcomes. I think that, you know, as you know, really delving into the data that Craig just went through, I think there's a lot that's encouraging here. I think the bottom line is that, not every patient in the study was selected in a way that would be a patient who would be given biologics. I think, you know, many of these people may have been not inadequately treated with prior medications and we see that in these careful sub-analyses now of patients who are, you know, for EoE, more severe as, you know, examined by inflammation, prior treatments, you know, presence of other strictures. You know, those people have a clear signal of response with the symptoms and symptom improvement. Similarly for patients with the EG/ EoD, when you look at the patients from not only the first set of centers in the original study, but interestingly, those who have biologic signs of worsening disease like the higher, you know, IgE. It's very interesting and I think incredibly encouraging to see a strong signal now in these more severe patients and highly selected patients, and these are certainly lessons that can be used going forward. Dr. Dellon, one of the conversations we had earlier this week was regarding parallel development programs, and you'd spoken about asthma and mepolizumab. Would you care to share that with everyone? Yeah, absolutely. I think this is a really important point to keep in mind, that patient selection is often key. You know, as I think, people know, mepolizumab is approved for eosinophilic asthma. The original studies of mepolizumab in a general asthma population were not positive. You know, it looked like the medication, in fact, did not work. I think, you know, what we can take from this, and then I should say that when they reanalyze the data, you know, secondary analyses like you just saw that, Craig, you showed, what came out was the patients with higher peripheral blood eosinophil counts were the ones who responded. Then the next study that they did focused on those patients, showed a clear benefit, and now that medication is approved. Here I think, you know, we have clear signals of what subgroups of EoE and EG/EoD patients to look at, you know, in these studies. We need the more highly inflamed EoE patients who have not been responding potentially to other treatments, who are not mild, who are not, you know, potentially just newly diagnosed and otherwise treatment naive. You know, we see for the EG/EoD patients, we see that, you know, perhaps we need to focus on slightly higher peripheral blood eosinophil counts, higher IgE levels, those types of things in the blood chronicity of their disease. You know, we see the strong effect in here, and that really confirms that in the right patient population, the medication is working. Not only is it improving the inflammation with its eosinophil and mast cell-targeted approach, but you're seeing the benefits of symptom improvements and in some cases in a dose response. That even goes to show, you know, the adolescent subgroup in the EoE study as well. I think the patient selection is gonna be key. Thanks, Evan. Do you have any comment on using a higher tissue threshold? I know we did that in a post-hoc look at our data. Any thoughts on that and how it really split the population out into what we believe were a less appropriate population where they had a questionable diagnosis of EoE versus those above our 24 threshold? Any commentary on that? Yeah. I think it's a really interesting finding. Of course, you know, it's set in the field that someone with at least 15 eos without, you know, in their esophagus with the right symptoms and without other causes of eosinophilia has a diagnosis of EoE. You know, that doesn't mean that patient who is, you know, very mild and who may just have 15, 16, 20 eos in one location of the esophagus is an appropriate candidate necessarily for a biologic. You know, there are a lot of data in the field that, you know, suggest that perhaps a more highly inflamed patient may be an appropriate one for these kind of studies. You know, the fact that this breakpoint, looking at around the 24-25 eosinophil threshold shows such a difference in the population, I think is interesting. You know, there are a number of study elements that can, you know, lead to higher eosinophil counts in patients. One is just requiring a more inflamed patient to be in there, almost as a proxy of, you know, their prior history, the extent of involvement of the condition in the esophagus, you know, and in some ways impacting on the severity. You know, other studies have, you know, mandated multiple segments of the esophagus being inflamed as well. I think, you know, if you compare the overall eosinophil counts in this study, you know, for the EoE patients of about 60, you know, compared to how you see the counts with stratification by this level and compared to what other, you know, count studies have done in the field, you see just a clear distinction. You know, it's not necessarily that these patients with the lower counts don't necessarily have EoE, but, you know, they just may not be the appropriate population for a biologic at this point. I think this is a really key finding, you know, going forward for other study designs. Thank you, Dr. Dellon. With that, I'll turn it back to Robert Alexander. All right. Thanks, Evan. I really appreciate it. Yeah, absolutely. Thank you. Okay, what I'm going to cover over the next few minutes is the scientific rationale for lirentelimab in inflammatory skin conditions, but specifically, we're talking about atopic derm and chronic spontaneous urticaria. Excellent. You know, within the literature there's a lot of data around mast cells and eos being involved in general in inflammatory skin diseases, and again, specifically with AD and CSU. These two conditions in particular are characterized by, of course, inflamed skin as well as chronic, moderate to severe itch. What we know is that eos and mast cells, among other cells, are active in these lesions, and there's a lot of crosstalk between those two cells as well as sensory neurons in the inflamed tissue. That crosstalk leads to the symptoms that the patient experiences. This has been characterized on a to the molecular level. IL-4, IL-13, IL-33, and MRGPRX2 are some of the molecules that have been shown to be involved in these conditions. We'll show you some data here shortly, where we've looked at lesional and non-lesional skin, and you see evidence of increased eosinophils and mast cells in those tissues, as well as those cells being activated. Then just a reminder that we do have data in patients with chronic spontaneous urticaria, as well as a small number of patients that have been in some of our studies that have had concomitant atopic derm. Next slide. Okay, what I'll cover here is we'll really focus on mast cell biology and activation, because we know we ablate eosinophils and in the presence of drug they're gone. What we're showing here is a number of the receptors that we know we specifically antagonize by engaging Siglec-8. To orient you to this slide, Siglec-8 is in the middle. As a reminder, Siglec-8 is an inhibitory receptor expressed on mast cells and eos. You can see our antibody AK002 engaging two molecules of Siglec-8, so it's dimerizing Siglec-8. Essentially that's activating the Siglec-8 receptor, and it's mimicking presumably the Siglec-8 and its natural ligand. What we know happens immediately upon cross-linking Siglec-8, you get phosphorylation of the ITIM motifs on the cytoplasmic side of Siglec-8. When they get phosphorylated, it creates docking sites for other proteins on the intracellular side of the membrane. Those proteins dock, they become phosphorylated, and as a consequence, become activated. One of the proximal events that happens thereafter the phosphorylation of the ITIM motif is a molecule called SHP-2 becomes activated, and that's a phosphatase, which means that it chews off phosphate from proteins that have been phosphorylated. The upshot of that is that when that happens, it downregulates the activating signal. We've recently published some information on this, and I'll show you that data soon. What happens here then is that when Siglec-8 gets activated, it starts to propagate an inhibitory signal, and we know that we inhibit receptors like the Fc epsilon receptor, which is the receptor for IgE on the mast cell. We know we inhibit toll-like receptor three. We know we inhibit MRGPRX2, which is a receptor on mast cells that actually binds a number of ligands. It's a bit of a promiscuous receptor. One of the ones, the ligands that you're probably familiar with is Substance P. We also know that we antagonize IL-33. Okay, next slide. Okay, this is some data that we recently published looking at the transcriptome of IL-33- activated mast cells. To orient you to this slide, on the far right is the transcriptome from a resting mast cell. You know, there's a lot on here. There's roughly 400 or so different transcripts that were analyzed in these cells. Just looking at it from a visual standpoint, on the far right is the resting mast cell. In the middle are mast cells that have been activated with IL-33 and given an anti-Siglec-8 antibody. On the far left you have IL-33- activated mast cells that have been given an isotype control to the anti-Siglec-8 molecule. What I want you to come away from here is that the middle panel and the far right panel have a similar profile. You see more of the down-regulated transcripts on the top half of the chart and more elevated on the bottom. You see that that's essentially the inverse of what's going on with the isotype control-treated cells. This is, you know, this is really interesting data. What it tells you is when we engage Siglec-8, we return activated mast cells to a more resting phenotype. Okay, next slide. Okay, this is a similar representation, but this is with IgE-activated mast cells. Another pathway of mast cells that is, you know, one of the key activating receptors on mast cells. Here what we're looking at is the phosphoproteome. As I mentioned in the first slide, the cartoon of the mast cell, when you engage Siglec-8, you kick off a cascade of phosphorylation and dephosphorylation events on the intracellular side of the cell. What we're looking at here is the total phosphoproteome of IgE-activated mast cells. Here, again, this is protein. The previous slide was transcripts. What we're looking at on the far right is the resting mast cell, and blue here indicates you know lower levels of activity. In the middle, you see mast cells that have been activated with IgE plus an isotype control to our anti-Siglec-8 molecule, and you can see an amplification of phosphorylation inside the cell. An indication that IgE has activated the mast cell, and the mast cell is going through the process of, you know, degranulating, and very likely producing de novo proteins. On the far right, you see the IgE-activated mast cell plus the anti-Siglec-8 antibody. Again, what visually you should take away from this slide is that the far right panel and the far left panel look very similar and essentially inverse from the middle panel. Again, at the protein level now, we're looking at evidence that an anti-Siglec-8 antibody returns an activated mast cell to a more resting phenotype. Okay, next slide. In this slide, again, going through the receptors that we know we specifically antagonize, we're looking at MRGPRX2. This is a model of MRG-mediated inflammation. In this experiment or this model, you give isotype control or lirentelimab at baseline, and about an hour later, you inject Substance P intraperitoneally, and then four hours later, you take the animals down. What we're looking at here on the right or the middle panel there is a measure of mast cell activation. So we're looking at CD63 expression. So CD63 is an activation marker on mast cells, and it typically is found on the luminal side of granules. So it's not available to stain using flow cytometry. When the cells become activated, those granules fuse with the plasma membrane, they invert and now disgorge themselves of the contents of the granule, but then you're able to stain for CD63. So again, evidence that the mast cell is active and degranulating. You can see a clear difference here between isotype control and lirentelimab. On the right is just another indication at the protein level that we inhibit inflammation, and we're looking here at two chemokines, MIP-1α and MIP-1β. Again, you see a significant reduction in those inflammatory molecules. Okay, lastly, we're looking at TLR-mediated inflammation in vivo. Again, a similar setup here where you're giving isotype control or lirentelimab, and shortly thereafter, you're giving an intranasal challenge of a TLR3 agonist, which is called poly(I:C). This is basically a sledgehammer to activate TLR3. The model progresses for three days, and then you look, take the animals down and evaluate them. This is a lung inflammation model. In the middle panel there was airway monocytes. You can see clear evidence of inhibition of recruitment of monocytes to the site of inflammation or challenge here. In addition to that, we're showing you here IL-6 and IL-1 beta, where we see a significant decrease in the levels of those cytokines. We also have data which looks very similar to that which we show inhibition of TNF, CCL2, and IFN. This data was published in Frontiers in Immunology. Actually, all the previous slides have the references at the bottom if you're interested in looking at the published data. Again, in yet another pathway and in vivo model of mast cell activation, we demonstrate inhibition of the mast cell through that pathway. Okay. Next, I'll jump into atopic derm and with the background that I just provided on mast cell inhibition, that's really the foundation for why we're interested in looking at lirentelimab in atopic derm and CSU, and we'll go through some specific data here on atopic derm. What we're showing you here are patient biopsies from folks that have atopic derm, where we've taken a biopsy of the lesional skin, and then directly adjacent to that, we've taken non-lesional skin. The upshot here is you see that mast cells and eosinophils are increased in numbers in the lesional skin compared to non-lesional. Then as you move into the middle panel, we're showing evidence of mast cell activation by measuring CD63, which is elevated in lesional skin versus non-lesional. Then also, we're looking at secreted products from the lesions, which includes CCL17 or TARC, as some of you may know it, and also CCL26 or Eotaxin-3. Again, just evidence that there, in these lesions, you have evidence of mast cell and eosinophil activation. Next slide. This is data from our severe allergic conjunctivitis trial, and this data is actually, I think, really interesting. Just to remind everyone, the SAC study was a study where we treated patients with chronic severe allergic conjunctivitis. These are patients that had inflamed eyes, you know, daily, essentially all year round. These patients were treated monthly with lirentelimab for six months. What we're showing you here are samples that we took of the tears from these patients. On the far left, we're just looking at IL-4. You can see the gray is baseline, and then we're showing two different time points during the study where we measure tears and look at the cytokines present, where you can see a clear reduction in IL-4. The far right light blue bar or column there is past the end of study, past the last dose, and you can see that the inflammatory markers go back up. You can see that same pattern for IL-13, for Eotaxin-3 and also MIP-1α. A clear drug effect in these patients over time and also then a rebound of those markers once the drug has come out of the system. Next slide. The data I just showed you is, I think, particularly important as you're thinking about atopic derm. What we're showing you here are some patients that came out of our ENIGMA 2 study and SAC study that had concomitant atopic derm. I don't wanna overinterpret it because it's relatively small numbers. I do think it's indicative of a response in patients with atopic derm with lirentelimab. On the right, you can see that there was a significant drop in the symptoms of atopic derm in the ENIGMA 2 study. Then we see a similar drop in the open- label SAC study from baseline in those patients. Again, it's a nice albeit a small data set, but a nice proof of concept in AD. On slide 56, this is our phase II AD study design. This will be a multicenter randomized double-blind placebo-controlled trial. We'll enroll patients that have had AD for greater than or equal to three years. They will have to be naive to dupilumab and other molecules that have been used in the space. It'll be 120 patients randomized 1:1, and patients will be getting 300 mg twice monthly for six months, and there'll be an open- label extension. The primary endpoint will be the proportion of patients who achieve an EASI-75 at week 14. Then there'll be some key secondary endpoints, including the percent change in EASI, as well as the proportion of patients that achieve an IgA of 0 or 1, and at least a 2, greater than or equal to a 2-point improvement in IgA at week 14. Okay. All right. On to CSU. Next slide, Alan, please. This is just a reminder that we completed a phase II-A study in chronic urticaria. This included not only chronic spontaneous urticaria in Xolair naive, it also included Xolair refractory. It also included cholinergic urticaria as well as symptomatic dermographism. This was an open-label study where we enrolled those populations. They were given monthly lirentelimab for six months. The primary endpoint was a change in the UCT from baseline, and then we also looked at UAS-7 and the components of UAS-7. Okay, so here's a portion of the data, and we've only included the CSU data here because that's the trial that we intend to run next in the urticaria space. On the left, you see the omalizumab-naive patients, and you see a very nice drop in the UAS-7 score, which again is a composite of itch and hives. Then on the right are patients that are omalizumab refractory. You see also a very nice response in patients that are truly refractory patients to omalizumab. These are patients that have been treated for up to a year on omalizumab and are found to be truly refractory. That was a very nice signal as well. This paper was recently accepted and will be published. Is it, Brad? Has it been published yet or is it still in press? It's been published. Is it? Okay. You, you'll be able to find this. This is a JACI paper, and it's available now. Okay, Alan, to the next slide. Okay, this is the phase II-B study that we intend to run. Again, this will be a multicenter randomized double-blind placebo-controlled study. It'll be in patients with active, moderate to severe symptoms. They have to have at least six months or greater duration of symptoms. They have to be refractory to the label indicated use of antihistamines, with a UAS-7 score greater than or equal to 16 and an HSS score, which is the Hive Severity Score of greater than or equal to 8 at baseline. They have to be omalizumab, dupilumab and benralizumab naive. It'll be roughly 100 patients, again, getting 300 mg every 2 weeks. Primary endpoint will be a change from baseline in UAS-7 at week 12, and we'll also look at the absolute change in ISS, absolute change in HSS, and proportion of patients with a UAS-7 equal to 0. Just to wrap all this up, there's a lot of evidence that mast cells and eosinophils are involved in a variety of inflammatory skin diseases. We're really focused here on atopic derm and CSU. We know that the AK002 has broad inhibition on mast cells and ablates eosinophils. We think there's a strong rationale for why the drug could work in these indications. We do have clinical proof of concept in CSU, and again, that small data set of atopic derm patients where it does appear that there's a signal there. Is Marcus on? Okay. All right. Next slide to introduce Marcus, Dr. Marcus Maurer. He's a Professor of Dermatology and Allergy at Charité in Berlin and is one of, if not the, world's expert in urticarias. We invited him here to give a perspective on chronic urticaria in general, but also with focus on CSU and lirentelimab in that space. Marcus, thanks for joining us. My pleasure. Thank you very much for having me. I very much appreciate too the opportunity to outline the huge unmet needs that we have in chronic urticaria and more specifically in chronic spontaneous urticaria. Look, I have seen chronic urticaria patients for the last 20 years, thousands of them. I know, and this is well described in the literature, that this is one of the most devastating diseases that you can have of the skin in the allergy field. It is really disabling in all parts of life, sleep, sexuality, performance. Everything is affected when you have this disease. Imagine you have 100 mosquito bites or 200 every day for years on end. These patients clearly need treatment that works, and we don't have that. The antihistamines we have don't even help half of them, even if we go off label, beyond label, up to four times the standard dose. The only other licensed treatment option is omalizumab, and we know that there are certain subtypes that do not respond to it, respond poorly. We clearly need better treatment options. That's why I'm very excited. You know, I've been excited about lirentelimab ever since I learned about this molecule. The idea of silencing mast cell is just very intriguing. I'm also a mast cell fan. I've been researching mast cells all my life. I know that most of the close to 100 receptors that we know of mast cells, all of them getting mast cells excited and degranulating and making them make inflammation. Well, there are only very few silencing receptors, and Siglec-8 is one of them, and it's a very powerful one. You have shown, and this is well described, that it doesn't shut down only one mechanism of these many activating mechanisms. It acts across the board. You know, it blocks IgE-mediated activation, which is important in chronic spontaneous urticaria. It blocks Mas-related G protein-coupled receptor X2, and many other pathways that lead to mast cell degranulation. You have to understand that this is the prototype mast cell-driven disease. Yes, there are also eosinophils that come to the lesions once the mast cells call them, but the initial driver of the whealing, of the itch, of the angioedema is degranulation of mast cells. Shutting that down is key. I was the head of the clinical trial that you just talked about and was very happy to see that you have such a strong effect size, high responder rates, and even in patients who had failed omalizumab. This is a true promise. Congratulations on getting the subcu formulation, which will enable the study that you already presented. We're very excited. You know, the whole urticaria field is very excited. We know that these patients are undertreated. A lot has changed. We have a global network of urticariologists, UCARE, Urticaria Centers of Reference and Excellence. The landscape has changed, but as long as we don't have better treatment options, well, we can counsel patients, we can include them in clinical trials, but we need better drugs. Lirentelimab is one of the most promising drugs that is currently under development for chronic spontaneous urticaria. Marcus, if you could you just comment on the unmet need beyond omalizumab? Yeah, sure. Look, we use omalizumab because it's the only thing we have right now. Other programs are under development. Why? Because omalizumab helps some patients, but not all. By far not all patients. There's safety concerns that especially in the U.S. limit the use of omalizumab. There is a long time to response and a significant subpopulation of patients. If you have this, you don't want to wait three, four, five, six months before you see an improvement. You want fast improvement like we saw for lirentelimab in those patients treated in that early study. Yes, other programs are under development, and I'm very happy to see that finally, chronic spontaneous urticaria is on the radar of partners, so recognized as a disease that is, well, on the one hand, a real unmet need in the space of chronic inflammatory diseases. You know, on the other hand, a true opportunity. When you look at the prevalence of this disease, you know, we speak of 1%, that's one in 100 people who have chronic spontaneous urticaria right now, increasing, and the rate of patients who today have uncontrolled disease, 80%. Eighty percent of all CSU patients on this planet have uncontrolled disease, despite availability of antihistamines and omalizumab. We have huge unmet needs beyond what we have today, and this is where lirentelimab comes in and can really help a lot of patients and help us because, you know, quality of life for patients with chronic spontaneous urticaria and chronic inducible urticaria is miserable. It's also not that much fun if you don't have, as a urticaria treating physician, the tools that you know could help patients get better. Yes, once again, this is a very promising strategy. I mean, if you want to, I'll be happy to also talk about what other programs are and how lirentelimab compares to them. It's certainly a front runner in what we hope will become a new chronic spontaneous urticaria treatment. Marcus, if you have a few minutes, that would be great if you could just elaborate on that a little bit further. Sure. Look, anti-IgE is a validated MOA. That's why omalizumab works, but it doesn't really help in the very severely affected type 2B autoimmune chronic spontaneous urticaria patients. The hope was on ligelizumab, which in an early study showed superiority over omalizumab. That doesn't seem to be the case now that we have bigger studies. We have dupilumab, which also reported positive results, and we think that this can probably work in those patients where omalizumab also works. The results have yet to be published. But this is also not the MOA that we need in patients who have autoantibody driven complement-mediated, essentially non-autoallergic chronic spontaneous urticaria. Today we can deplete mast cells, very interesting, with an anti-KIT antibody. This is early days. It provides proof of concept that mast cells really are the key drivers of chronic urticaria, and we learn a lot from this approach. It is not a mast cell-specific depletion. We also hit KIT-positive cells that are not mast cells. The prospect of silencing rather than taking them out altogether is certainly very attractive. We have some other programs that are even earlier on TSLP. We have BTK inhibitors. All of them have their benefit for sure. I encourage all of them because there's plenty of space in this huge disease with many patients untreated and many patients not responding to the treatment options we have. There will be enough space for more than one new novel treatment. We also have to look at a chronic inflammatory disease where patients have their disease for five, 10, 15 years. Safety is key. Looking at BTK inhibitors, for example, where we do see safety signals from the development or looking at other diseases that were treated with them and have a different profile. You really have to weigh safety and tolerability with efficacy. This is where lirentelimab really is a champion to come for both of this. The patients really like to be in that study. They keep asking us when they can have this again. It shows that we are learning a lot by these different approaches, and we need different approaches. Silencing of mast cells with the added benefit of depleting eosinophils is a very promising approach. Thank you, Marcus. One final question from our end. Given the prevalence that you've been speaking about, do you have any thoughts as to why patients are still not getting diagnosed and why the treated population is not higher than what it currently is? It is high. It is out there. We also know from studies performed by the U.K. network that up to 50% of patients in the current situation do not see physicians. Why? Because they had failed them. It will take building of confidence to bring these patients back into the doctor's office. What will do that? To be able to tell them we have something that's better than the old sedating antihistamines that you tried and didn't work for you. We also see that now that expert centers are working together, we do get much better awareness, much better education, so specialists, including derms and allergists, but also family doctors, GPs, they do see urticaria as something that is treatable, that they understand, that they welcome in their office. This wasn't the case ten years ago, where physician colleagues out there didn't really understand what it was and why patients get this and confused it with allergies. Today, we have a good guideline. We have good understanding of the pathogenesis. If we had good treatments, well, that would bring patients back and get doctors on board to help these patients that currently are not receiving the treatment that will help them to control their chronic urticaria. Marcus, I really appreciate your time. Thanks for making time this evening, your time for us, and thanks for your, you know, your thoughtful commentary on this. Sure. Thank you very much for bringing me on board. Anyone who has any questions on urticaria, please, feel free to reach out to me offline. I'll be very happy to go into details. Great. Thanks again, Marcus. Really appreciate it. My pleasure. Take care. Okay. Bye bye. Bye. Okay. What we'll do now is switch gears from lirentelimab, and Brad will quickly go through our pipeline strategy. How we think about the drugs or the molecules that we bring forward in development, and then he'll go into some detail on the newest molecule that's working its way toward the clinic that we're very excited about. Brad. Cool. Thanks, Robert. As Robert mentioned, I'll be going over our pipeline strategy for R&D as well as our latest pipeline program called AK006. Most of the therapeutic landscape around inflammation has really been focused on targeting individual cytokines that are thought to drive chronic disease. While this approach has shown to be effective, most of these cytokines are actually made by a small number of cells that could be targeted directly. At Allakos, we're interested in targeting these cells directly using the CD33 subfamily of Siglecs, which is shown on the right. These are a group of inhibitory receptors that are selectively expressed on key disease-driving cells and are mainly found within humans. Using antibodies, we have an opportunity to either agonize or neutralize these Siglecs to modulate cell activation. In settings of chronic inflammation, we're interested in agonizing these Siglecs to induce inhibition of key disease-driving cells, which is what we do with AK002. Whereas in tumor settings, we're interested in neutralizing these Siglecs to induce activation of cells that can drive antitumor function. By targeting these Siglecs, it really gives us an opportunity to selectively modulate cell activation in a number of different disease settings. Based off the therapeutic opportunity that exists from the CD33 subfamily of Siglecs, we've expanded our pipeline to include two new programs, AK006 and AK007. AK006 is a Siglec-6 antibody that selectively targets mast cells and was really optimized based off our learnings from AK002. While AK002 has potent and broad mast cell inhibition, as Robert, Craig, and Marcus spoke to, it was never really optimized for its mast cell activity. We went back to the CD33 subfamily of Siglecs and found that Siglec-6 is selectively expressed on mast cells and can modulate mast cell activation in a way that's not seen with AK002. We developed AK006 to selectively target mast cells in a way that's not seen with current mast cell-targeting molecules. I'll be walking everyone through some of these interesting slides in the next few minutes. Mast cells are now recognized as key drivers in a number of different disease settings. One of the features that make mast cells so pathogenic is that they express a wide number of activating receptors on their cell surface that are thought to drive chronic disease. In support of this, there are a number of molecules, as you can see on the left, that target these activating cell receptors found on the mast cell or mast cell-derived mediators. However, none of these molecules selectively target the mast cell, and on top of that, most of these molecules are not able to block multiple modes of mast cell activation. This is problematic because it can cause either incomplete mast cell inhibition or off-target tox. Based off our expertise in Siglecs, we identified Siglec-6 as an inhibitory receptor that's selectively expressed on mast cells and can modulate mast cells in a way that's not seen with current mast cell molecules. Since Siglec-6 is only found within humans, one of the first things we did was characterize its expression at the human level. To do this, we processed multiple human tissues down to single cells, and we used flow to find major cell populations within these human samples, which is shown on the left. When we looked at Siglec-6 protein levels within these cell populations, we found that Siglec-6 was only expressed on mast cells, as you can see on the right. These findings really got us excited because it demonstrated that Siglec-6 is a selective mast cell receptor that could be used as a therapeutic target in a number of different mast cell-driven diseases. To target Siglec-6, we developed AK006, which is a humanized anti-Siglec-6 antibody that selectively targets mast cells. On top of its selectivity, it has a unique mechanism of action that differentiates the cell from other mast cell-targeting molecules. As you can see on the left, when AK006 binds to Siglec-6, it activates an ITIM phosphorylation cascade that drives broad mast cell inhibition of both IgE-dependent and independent modes of mast cell activation. On top of its mast cell inhibition, we also have data showing that AK006 can lower mast cell numbers via an Fc-dependent mechanism. AK006 really gives us an opportunity to selectively target mast cells in a way that's not seen with current mast cell targeting molecules. One of the first things we did with AK006 is we tested its function against IgE-mediated mast cell activation using a human tissue mast cell activation assay that's shown on the left-hand side. In this assay, human tissues are processed down to single cells, and we activate mast cells through the IgE receptor pathway and look at mast cell activation using CD63. CD63 is a well-known mast cell activation marker that's usually found on mast cell granules, and upon activation, fuses with the plasma membrane. As you can see on the right-hand side, AK006, shown in orange, potently lowered CD63 levels on the mast cell surface, so much so that it brought it back down close to baseline levels. AK006 was more potent at mast cell inhibition than AK002, which got us really excited because we know that AK002 has clinically relevant mast cell inhibition. If we're able to expand on that with AK006, then we have a really interesting asset to take forward in a number of different mast cell-driven indications that could complement AK002. Next, we tested if AK006 could inhibit mast cell activation in vivo using a systemic anaphylaxis mouse model that was done in humanized mice. Here, we focused on humanized mice because Siglec-6 is only found within humans, and these mice are actually engineered to have human mast cells that express Siglec-6. In this model, we activated mast cells through the IgE receptor pathway, which in turn induced systemic anaphylaxis, which is shown on the left-hand side. Mice dosed with AK006, shown in orange, demonstrated a complete inhibition of this anaphylactic response. In addition, we also looked at known mast cell-derived mediators that are thought to drive anaphylaxis in these mice, which include active tryptase, chymase and histamine, in which all of these were induced in mice that are undergoing anaphylaxis and lowered in AK006-treated mice. These data really built upon the data on the previous slide and show that AK006 can inhibit IgE-mediated mast cell activation both in vivo and ex vivo. We also know that mast cells can get activated by modes independent of IgE. One such mode is through KIT, which is a potent mast cell-activating receptor that's currently being targeted by a number of different molecules. While KIT is an interesting mast cell target, it's also expressed on certain stem cell populations and germ cells, which could drive off-target toxicities mast cell-driven diseases. We are interested if AK006 can more selectively target KIT-driven mast cell activation. We set up a KIT-mediated mast cell activation model in our Siglec-6 transgenic mice, which are mice that are engineered to express human Siglec-6 on mouse mast cells. We activated KIT using stem cell factor, which is the natural ligand for the receptor, which induced potent mast cell activation, as shown by elevated CD63 expression, as well as through a number of different cytokines and chemokines. Mice treated with stem cell factor and dosed with AK006, shown in orange, demonstrate almost complete inhibition of this KIT-driven mast cell activation, which included downregulation of CD63 on the mast cell surface, as well as reduced levels of cytokines and chemokines. These findings really demonstrate that AK006 can induce broad inhibition of mast cell activation without having the off-target toxicity with molecules that specifically target KIT. Based off the potent mast cell inhibition seen with AK006, as well as the known pathogenic role of mast cells in a number of different chronic skin disease, we next tested AK006 in a model of contact dermatitis in our Siglec-6 transgenic mice. In this model, mice are sensitized and challenged with DNFB, which is a hapten that causes local skin inflammation, as you can see on the right-hand side. Mice challenged with DNFB and dosed with AK006, shown in orange, demonstrated a robust inhibition against this hapten-mediated response, which included reduced swelling of the ears, as well as reduced levels of cytokines that were pumped out in ex vivo cultured ears, which included IL-4 and TNF. These findings really got us excited because it demonstrated for the first time that selectively targeting mast cells with AK006 can reduce skin inflammation in a model of contact dermatitis that is frequently used as a surrogate to mimic chronic skin diseases such as CSU and AD. These findings really highlight an opportunity for AK006 treatment in a number of different chronic skin diseases. On top of mast cell inhibition, we also have data showing that AK006 can lower mast cell numbers. On the left-hand side is an ex vivo assay in which we cultured human tissue mast cells with and without activated macrophages. In the presence of activated macrophages, we found that AK006, shown in orange, lowered mast cell numbers relative to the IgG control or AK002, shown in blue. To test if these data would translate to a mouse model, we again used humanized mice, as these mice are engineered to have human mast cells that to express both Siglec-6 and Siglec-8, and we gave these mice multiple doses of either AK006 or AK002. As we saw with the ex vivo assay, AK006-treated mice had lower mast cell numbers relative to the IgG control or AK002, demonstrating that AK006 can directly lower mast cell numbers in a mechanism that's not seen with AK002. These findings really start to paint a picture in which AK006 may have this dual mechanism of action against mast cells and was just able to induce broad inhibition of mast cell activation and also lower mast cell numbers. We're super excited to push this AK006 program forward as it does represent the first mast cell-specific molecule that's in development. This is a very important feature for AK006 as it avoids off-target effects that's seen with a number of different non-selective molecules that are trying to target mast cells such as KIT. On top of its selectivity, AK006 has a unique mechanism of action that differentiates itself from other mast cell-targeting molecules, which includes broad inhibition of mast cell activation and also mast cell reduction. We've just wrapped up our non-GLP tox studies with the first in human study planned for the first half of 2023. Thanks. I'll hand it back to Robert and Baird. Okay. Thanks, Brad. Baird will give a financial update now. Good morning, everyone. I want to update you on our cash position, spend reduction efforts, and cash runway. We exited 2021 with $424 million of cash and investments, reflecting $83 million of cash used in the fourth quarter. This fourth quarter spend landed where we expected and includes the planned ramp-up in manufacturing costs in advance of our previously planned 2023 commercial launch. As the team has shared with you today, the clinical study data points toward a path forward in EGIDs as well as atopic dermatitis and chronic spontaneous urticaria. As a result of our updated clinical timelines, we have made a number of changes to our operating plan and cost structure to reflect the delay in commercialization. First, we scrubbed our go-forward plans and removed internal and external expenses related to commercialization. We also reduced our employee base by 35%, returning to 2020 headcount levels. Next, we renegotiated contractual arrangements with various third-party manufacturers and other vendors to substantially reduce our future obligations in exchange for one-time cash payments. The net results of these actions is a first quarter expense and cash used outlook being higher than our historical levels. These one-time cash payments for severance, employee retention, and contract renegotiation costs are anticipated to be approximately $150 million, with the bulk of these payments occurring over the next few months. On the topic of clinical development pathway, we are delaying the start of our phase II asthma study to conserve near-term cash and concentrate our capital on conducting phase II clinical studies in atopic dermatitis and chronic spontaneous urticaria, with data readouts projected for the second half of 2023. As for our EoE plans, we anticipate holding an end-of-phase II meeting with the FDA in the second quarter of this year. Following that meeting, we will share more details regarding our phase III EoE study design and timelines. In summary, we believe that our updated operating plan provides us with the cash runway into early Q1 2024 and positions the company to achieve a number of important milestones. Although the Q1 2024 cash runway assumes no additional capital is raised, we will continue to opportunistically seek additional capital through future financings and/or business development arrangements. I hope this update provides additional financial insights, and I will now turn the discussion back to Robert. Good. Thanks, Baird. Okay, so just in closing here, we'll take a snapshot of the development timeline, and Baird ran through most of this just a second ago. As Craig mentioned and Baird just now, we are excited about the EoE data, and the next step there will be to go have an end of phase II meeting with the FDA with our expectation that we will initiate a registrational study in EoE in the near future. With regards to EG and EoD, we think we have our arms around what went wrong in that study as well. Similar to EoE, it came down to patient demographics. We will wait to get the data from the EoDyssey study to have the benefit of that information. As Craig mentioned, once we have that, we'll analyze it and put it in the context of the ENIGMA 2 study and then go talk to the FDA about next steps. We are ready to initiate a CSU study. We did initiate the atopic dermatitis study toward the end of the year, but that will start to ramp up more in the coming weeks to months. Those two studies will begin enrolling patients very soon. As Brad outlined, we're very excited about the AK-006 molecule. We expect that to be in single and multiple ascending dose studies in Q1 of next year. We'll update the market on that as well as other pipeline programs as they get further along in development. Okay, that was the end of our planned remarks, so we will open it up to Q&A now. Thank you. We'll now be conducting a question-and-answer session. To ask a question, you will need to press star one on your telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. Our first question comes from the line of Joseph Thome with Cowen and Company. Hi there. Good morning. Thank you for taking our questions. The first one in EG, EoD and EoE, it looks like, you know, obviously with the baseline eosinophil changes and all the things that you pointed out, there's definitely differences, but it looks like the baseline symptom scores were relatively consistent no matter how you cut the data. I guess, are these the right symptom measures to be measuring these patients, or do you think definitely kinda captures disease? Then maybe, second question, in terms of compliance, were all the sites relatively consistent with compliance or were the ENIGMA 1 trial centers maybe a little bit better with drug handling and administration or anything like that? Thank you. Sure. Yeah, you know, symptoms, I think it's been pretty well described in EoE that symptoms are not necessarily a precise measure of or objective measure where you can compare one patient to another in terms of severity. I think that's one of the, you know, maybe the painful lessons here is that, when you strictly go by the guidance, with symptoms followed by a biopsy with histology, it doesn't necessarily weed out patients that may have a related condition like GERD or GERD with allergy from, mild EoE. Certainly it doesn't distinguish between someone who has severe EoE, and by that I mean someone who has higher tissue eos, higher peripheral blood eos, and higher IgE, where they could still have the same burden of symptoms. Unfortunately, symptoms don't correlate. I think we also again learned that with the EG study. Craig, I don't know if you wanna comment on that, and then the other question was regarding sites and compliance. Yeah. Robert, I think you're exactly right, and I think we're not the first or the last to necessarily see a little bit of a disconnect between symptoms and histology. So that's exactly correct. In terms of the compliance issues, we've seen no real issues with compliance, whether we compare ENIGMA and non-ENIGMA sites. I think it really boils down to the population in hand at those centers and the patients selected to enter the study. As we've alluded to, it really comes down further to the patients having the right characteristics and demographics. Maybe, yeah, maybe just a little more color on that. I, as Craig said, it's, you know, when you're a site that diagnoses and manages these patients as a matter of your practice, I think you have a much better sense of what's going on with those patients and what they've, you know, what their patient journey has been. I think at some of these other sites, some of these patients technically met the qualifications. It's very likely they had not tried and failed standard of care, and unfortunately, there wasn't that thread of consistency in that with the care of those patients. You know, certainly, that's something that we will rectify in the studies going forward. Great. That is very helpful. Thank you very much. Sure. Thank you. Our next question comes from the line of Thomas Smith with SVB Leerink. Hey, guys. Good morning. Thanks for taking the questions. Just wanted to ask if you've done any analyses in KRYPTOS or ENIGMA 2 correlating eosinophil reductions in these studies with reduction in symptom scores. Maybe a question for Dr. Dellon, if he's still on the line. Just wondering if you can comment on whether there's anything in the dataset or these datasets that changes the way you think about eosinophils as a driver of patient symptoms in these diseases. Sure. I'll have Craig answer the first question, Thompson. I think Evan, you might be— I'm still here. Oh, okay. Great, Evan. I'll let Craig jump in on that first part, and then maybe you could handle the second one. Thanks. Yeah, you can imagine we've looked at this data a lot of different ways, and I think I'll just start by saying that in general, higher eos scores did correlate better with improvements or changes in symptom scores. Maybe I'll hand it over to Evan to continue the response. Yeah, I think it's a great question, and it gets to really the drug mechanism and the disease. But I don't think there's any question that the eosinophils are not key drivers of disease as effector cells. I think the issue here. I think what we would have seen if they were not key drivers is we would have seen no symptom response. We saw across the studies, but we see symptom response, and we see the symptom response in the subgroups that have more severe kind of disease metrics. I think the issue here is that you know mild levels of eosinophils you know in a patient who may not have a long-standing diagnosis or who may not have had other treatments are not a good you know it's not a good population to have a biologic. There's been a couple of other studies including one biologic where if you look at the overall population you know there are trends towards symptom improvements. If you look at say a steroid refractory population only there's a very strong signal for symptom improvement which goes with the histologic improvements as well. I think it's still an appropriate marker to look at for sure. Okay. Yeah, appreciate that color. Wanted to follow up on the symptom improvements. Have you conducted any analyses looking at symptom improvement over time? Maybe you could provide some color on whether the kinetics here were similar to those that were observed in ENIGMA, where you saw a pretty dramatic improvement within the first couple weeks. Did you see anything different in terms of the timing of symptom improvement? Yeah, I think it was fairly similar. Again, when you identify the patients that were appropriate for the study, you see similar kinetics of response. As I showed, at least in the interim look at the open- label extension data, we see evidence of deepening of that response, certainly durability, but even a suggestion of deepening of that response over time. Okay. Maybe one last question on the atopic derm study. I think the design that you laid out today is perhaps a little bit different than what's laid out on clinicaltrials.gov. Can you just talk to, I guess the choice of the 300 mg Q2 week dosing here relative to, I think in your phase I studies, you've been looking at monthly dosing, and I think as laid out on clinicaltrials.gov, you were also kind of contemplating monthly dosing. Any additional color you can give on how you're thinking about Q dosing? Yeah. The studies that we had originally planned were gonna be placebo, I believe, a low dose and a high dose. You know, after we got the data and I think part of this is, you know, if you believe that, you know, more drug here seems to be better. These are proof of concept studies, so what we wanna do is to make sure the patients are getting and maintaining high dose levels. The 300 mg twice a month will definitely cover the trough levels that we modeled with IV. It's simply a matter of making sure that there is no question as to whether or not the patients are being exposed to enough drug. Assuming that those proof of concept studies are positive, we very likely will come back with, you know, for example, you'll have the 300 mg twice a month, and then you'll have 300 mg once a month, and we'll manage the dose response there in the subsequent trial. Okay. Got it. Makes sense. Thanks for taking the questions, guys. Sure. Thank you. Our next question comes from the line of Sam Slutsky with LifeSci Capital. Hey, good morning, everyone. Thanks for the presentation. Couple questions from me. I guess first, if Dr. Dellon's still on, can you discuss more in depth the history of topical steroids and those initial failures in EoE, what was learned as it comes to study design, and then the outcomes of topical steroids once those changes were implemented? Sure. For the topical steroids, you know, one of the initial ones in the U.S. at least, was the budesonide suspension in their pediatric study. It had very similar results to what we're seeing here with a dose response of 90%+ for histologic response in that study. Both the active arms and the placebo groups similarly having a good improvement in symptoms, so a very high placebo symptom response rate. Similarly in the budesonide dissolvable tablet, their phase II study, where there was an initial two-week induction phase. Again, they saw 90%+ histologic response. When you look at the symptom response curves over their study in their phase II, you could see that there was a placebo response that was similar to the symptom response as well. You know, some of the things that were implemented there were, you know, patient population. The pediatric study had more of a multi-symptom, sort of non-specific, symptom measure without a clear threshold for study entry. There was a duration issue in the other study in Europe, where it was two weeks only, and they extended it out for their next sets of studies. Both of those did not use, you know, validated instruments. When you look at some of the subsequent phase II and phase III studies in those with those esophageal-specific steroid formulations, you do see significant symptomatic responses and improvements between the active arms and the placebo arms. I think, you know, those studies also had some slightly different inclusion criteria, you know, than this one. I think in general, more severe patients, you know, were enrolled in those studies. I think that's some of the adjustments that were made. Those are examples of really lessons learned that in subsequent studies were good results, I think. All right. That's helpful. I guess for Dr. Dellon as well as the Allakos team, you know, with some of the findings in the EGID studies being patients with higher eosinophil counts and higher IgE levels being more likely to respond to AK002, how do you think about epidemiology when factoring this in? Yeah, Sam, are you referring to, like, the 019 study? The epidemiological study? Yeah. In terms of just, you know, selecting for patients with higher eosinophil levels or IgE, does it change the epi much, or is it more so that patients were included who weren't truly kind of EoE or EGID patients? Well, you know, that's a little. Let me answer it this way. I think what we did do, because, you know, we had the same, a similar question. When we ran the epidemiological study, you know, patients had to be symptomatic on the TSS, and then they were biopsied and diagnosed with EG or EoD based on the thresholds that we established with, you know, our key opinion leaders in the FDA. At the time, we did not include in this, in that characterization things like peripheral blood eos and IgE. What we did do is we went back and looked at that data and used, you know, different thresholds for those patients that we identified in the epidemiological study. Using a you know strict cutoff of IgE, for example, we could. You get roughly half the population is above that IgE level and half would be below it. If you wanted to use that as a way to you know segment that population into a biologics indicated population versus not, or perhaps maybe a better way to think about it would be a you know clinical trial population, you'd reduce it by half. You'd be going from 2 million-4 million people as an estimate to 1 million-2 million people or so. I think it's a slightly nuanced point because it's— ou know, we don't know what would happen on the commercial side. If you did say, "Hey, you can't treat anybody that's under that threshold," it'd be about half that population, but it's still a, you know, a really substantial population. Okay. Just last question from me. Just any view yet on the mechanism for why targeting Siglec-6 results in a more potent effect on mast cells than Siglec-8? Like, anything on the intracellular signaling pathways or anything elucidated there yet? We're working through all that data now, and there'll be more to come on that. Brad, I don't know if you wanna— Yeah, that's about right. Yeah. Yeah. The why it reduces. I mean, clearly there's a difference in the signal that's generated through Siglec-6, even though it's coming from, or it's propagated by ITIMs. That's not the same thing as saying that the quality of the signal will be the same between Siglec-8 and Siglec-6. We're working through elucidating those pathways, but clearly we know it inhibits KIT, for example, whereas Siglec-8 doesn't. It's not magic. There is a difference there. Got it. That's helpful. All right. Thanks, everyone. Thank you too. Thank you. Our next question comes from the line of Tim Lugo with William Blair. Thanks for taking the question. Can you talk about maybe how you can change the stat analysis plan or make any sort of protocol amendments to EoD study to encapsulate kind of all these learnings you're getting from the phase III EGID study? Yeah. Tim, I'll take a stab, and then maybe Craig. Yeah. I mean, it's a really good question. So, you know, hypothetically you could do something like that where, based on the learnings from ENIGMA 2, you could modify the statistical analysis plan. It has not been finalized and doesn't need to be finalized right now. It just needs to be finalized before you break the blind. So we could modify the SAP to only include patients that have the requisite qualities that we identified in ENIGMA 2. So that's something you could hypothetically do. I don't think we've reached a decision on that yet or not. Craig, do you have an— Yeah, no, that's exactly right, Robert. Certainly we've looked into that. Obviously, as I mentioned, we've looked into the baseline demographics and characteristics of these patients and can identify a group that certainly seem more like those that came from the ENIGMA centers. We've done that. Yeah. Okay. That makes sense. I guess going back to some of the subgroup analysis you showed, the adolescents obviously had very strong signals in a, you know, kind of 20% of the total subgroup. Could that be due to the weight of those patients? I mean, we kind of saw a clear low dose, high dose difference. Can you just maybe talk about your thoughts around dose now that you've scoured all of this data, and then maybe the confidence in that 300 mg Q2W dose going forward in the other indications? Yeah. Maybe I'll address the EoE study in the adolescent. The good thing was that we were weight-based dosing, so when you saw the high dose and low dose, it was 3 mg/ kg and 1 mg/ kg respectively. From an adolescent to adult, you know, look, it really is the same thing. They were just dosed appropriate for their weight. I'll turn it back to Robert for the 300 mg fixed dosing. Yeah. Tim, obviously it does—w hen you're giving a fixed dose, you can't have, you know, higher or lower exposure based on weight. Typically, our patients have been pretty consistent in weight, so we know the exposure. Like I mentioned, we're trying to make sure we cover trough levels in the studies. We're, you know, doing what other sponsors have done when going into proof of concept. We wanna make sure that we give the molecule the best chance to succeed, and then we'll figure out if we do have a positive trial, then we'll do a dose range to see, you know, exactly where efficacy would break down as a function of dose. That's how we're approaching that. Okay. Maybe lastly for the EoD study, do a lot of those patients being enrolled have a history of IBS? It seems like that's kind of a glaring difference between the ENIGMA. Yeah. Some of that, you know, the analysis on EoD is just starting 'cause we've been obviously focused on other things over the last few weeks. I don't know is the short answer, 'cause we haven't specifically looked at that. I wouldn't be surprised. As Craig mentioned, I believe there's relatively few ENIGMA 1 sites that participated in that study. You know, without the benefit of looking in detail at the data, I would suspect that those patients will likely look very much like the patients that were enrolled in the non-ENIGMA 1 sites in the phase III program. You know, again, because I suspect that many of these sites probably don't necessarily treat and manage these patients in a way that represents a significant part of their practice. I suspect you might see patients coming in with that technically meet the definition, but perhaps haven't tried and failed standard of care or perhaps are being misinterpreted as EGIDs. We'll just have to. We're gonna jump on that, you know, now and get ready for those results. We'll have more information on that for everybody in the, you know, coming weeks or months. Okay, great. And maybe one last question, just, could you talk about the higher-eos patients? Are those patients meaningfully different than the lower-eos patients or is it just a similar patient at a different time of the course of their disease, you know, during an active flare which may be, you know, if it's a long trial, maybe that normalizes? Or is that truly a different patient with just more severe flaring? Yeah, no, it's a really good question. I don't think the field necessarily understands that right now. I'd say generally when you look at the patient demographics, higher eos in the tissue, higher peripheral blood eos and then higher IgE which then reads on the mast cell component of our mechanism because IgE is secreted by B cells, but then it binds the high affinity IgE receptor on mast cells and that's what triggers, you know, that's one of the key triggers for mast cell activation. So that reads onto the mast cell. So it's really the combination of those things that circumscribes a population that responds quite well to the drug. The patients that don't have those attributes or are significantly lower on those, they could be patients that perhaps are earlier in their disease course. They could be patients that may have another explanation for the eosinophilia. I think what we kinda learned in a very painful way is some of those patients, you know, just with seeing a physician and, you know, a single dose of a steroid had dramatic benefit, tells you that those patients were not the ones that we were looking for because we know from ENIGMA 1 that those patients, even though they, you know, 34% of the placebo patients received Solu-Medrol during that study, had no effect on symptoms and had no effect on histology. They're really different patients. Why they're different, I don't think anybody knows right now, but when you're thinking about, you know, conducting a trial and looking for the right people, high blood eos, high tissue eos and high IgE circumscribes the population that we'll be identifying, you know, going forward. All right. Thank you for all the clarity. Yep, sure. Thank you. Our next question comes from the line of Maury Raycroft with Jefferies. Hi, thanks for taking my questions. Kind of following up on some of the earlier ones. I'm wondering for EoE, you talked about the tissue eosinophil cutoff at 24, which seems to be supported by the Rothenberg reference in the subpopulation analysis from KRYPTOS. Would you wanna confirm this in another phase II prior to running a phase III? Or is part of your objective of the end of phase II meeting to see if you could incorporate this finding into your, subcutaneous phase III EoE design to use that as a registrational study? Yeah, no, I mean, look, certainly we expect the EoE study to be positive. I mean, there's no two ways about that. We also expected to not have patients that didn't have, you know, EoE. We didn't expect them to be in the study. Whether the study met top line or didn't, the next unless it was just there was absolutely no signal. But even if the study were positive top line, the next step would be to go talk to the agency about an end-of-phase II meeting. The EoE, I think given the fact that we and you know Evan and others that have seen the data are excited about it and believe that you know we identified the cause of the issue, our approach would be to go to the agency and discuss a registrational study based on the findings. I think Craig alluded to this and you know, Craig or Evan can jump in on this, but you know other sponsors have added, I don't think they spend a lot of time talking about it, but they do have several hurdles that patients have to get over in order to get into the study. You know, what we had done was simply use the FDA guidance and unfortunately about 17% of the patients, although they strictly met it, probably were not EoE patients and regardless of that, certainly weren't the patients that we wanted in the study. Our approach would be to look at 24 as being a t issue eosinophil hurdle that essentially will eliminate these patients or dramatically eliminate them from entry into the study, as well as some other key exclusion criteria. I don't know, Craig or Evan. Yeah, I'll just add, and then Evan, if you wanna go. I mean, certainly one of the other ways is to require 15, a peak field of 15 in at least two regions of the esophagus. In particular, I think the proximal esophagus has been used to help differentiate reflux, for example, from true EoE. Evan, any other thoughts on that other than what we've articulated? Yeah, no, I think that's right. I mean, I think the general thing is just ensuring a more inflamed population. Typically other studies have done this by requiring more than, you know, two or more levels of involvement in the esophagus. That often gets you peak eosinophil counts in the 80-140 eos per high-power field range, so highly inflamed patients. I think you know, the other thing that gives you the more severe patients would be a little bit more formally requiring some prior failure of treatment, even if that's just something as simple as PPIs. These things will all be considered. I think when you look at this population overall and seeing the very low other treatments that those patients with the low eosinophil counts have had and the minimal amount of dilation compared to, you know, difficult to treat populations that have had a lot of dilation in some of the other published studies, that just reflects on some patients being too mild, you know, in this study. Got it. That's helpful. I guess just to follow up on that, could these findings be incorporated into the planned subcutaneous EoE phase III study? To make that a registrational study? For sure. We, you know, we'll incorporate, as Evan said, there are a number of ways. Look, the bottom line is, you know, you wanna circumscribe the right population in a clinical study to give you the best chance to be successful. Obviously, we'll put more guardrails. You know, we had them in, the patients got in that shouldn't have. We'll do more to ensure that that doesn't happen. Of course, that will be included in the registrational study. Got it. Okay. Just a quick question on atopic derm. Just wondering if you could talk a little bit more about the rationale behind picking the timing of the endpoint at 14 weeks, and what benchmarks for efficacy are you guiding to in your readout from that study? Yeah. I think 14 weeks seems to be kind of a standard look in terms of what the readout, and that's kinda optimizing for placebo response as well as where we think we're gonna be the most active. For benchmarks for efficacy, how are you guiding to that? Well, you know, I think we would hope to see something comparable to what dupilumab, you know, or others that have gone through there. That, I think, is the benchmark that everybody's aiming for. Got it. Okay. Okay, thanks for taking my questions. Sure. Thanks, Maury. Thank you. Our next question comes from the line of Mike Ulz with Morgan Stanley. Hey, guys. Thanks for taking our questions. Maybe just one on ENIGMA 2 and a follow-up to some of the earlier questions related to symptom score. Just curious if you had also looked at TSS-8, where you include the diarrhea and vomiting domains, and curious if you saw similar trends there? Yeah, there's really no difference whether you look at TSS-6 or TSS-8. It really just came down to this milder population getting into the study and having the exaggerated placebo response. Yep. Gotcha. Maybe just another question with respect to the EoD study that's ongoing, and you'll have an update mid-year. You know, you've mentioned just given similar population to ENIGMA 2, it's probably unlikely to be successful. Just curious if there's anything specific you're hoping to learn from that study that you haven't learned yet, or is it more just waiting to have that data so you have a larger data set when you go speak to the FDA? Well, yeah, I mean, it's definitely that. There's a couple things we could learn. I think it was Tim that asked the question about looking at the, quote, "the right population." Well, you know, we've just begun turning our sights toward AK002-021. We certainly still have the opportunity if we decided to look at a specific population within that study that meets the criteria that we've identified from the ENIGMA 2 results. We'll consider that. Then the other thing that, you know, the key reason we did the study was to look at the distal GI tract, so to look at the terminal ileum, colon and rectum, and characterize the eosinophil counts and mast cell counts in that portion of the gut so we could, you know, answer the question of whether or not you find a lot of eosinophilia in the lower bowel and then characterize what happens to that. That's the other, you know, important piece of that. That really is independent of whether the trial is successful or not successful. Those are the key things that we hope to learn from that. I gotcha. Thank you. Yeah, sure. Thank you. Our next question comes from the line of Paul Choi with Goldman Sachs. Hi, everyone. This is Charlie on for Paul. Thank you so much for taking our questions, and thanks for all the updates. I guess first I had a question regarding the generalizability of what we're seeing with this post hoc analysis with the EGID study results. You know, we're seeing lirentelimab kind of demonstrating more of an optimal activity in the more severe populations. Should we be c onsidering that this might also be true for other inflammatory diseases that are being looked at for lirentelimab development? I had a follow-up question as well. Yeah. I don't know that I'd quite characterize it that way. Certainly, in this particular study, when you take patients that I think are pretty convincingly not the target population out, you see a very nice signal. I think the way that I think we and, you know, Evan and others are thinking about this, that is the population of interest. So it's not this population that got into the study that frankly shouldn't have, are not patients that would be biologics indicated. So it's the other group that is. It is gratifying, you know, I think. As you look at patients that get more and more severe, you see the drug working there as well. That population, the 228 out of the 276, that's the group that is our target population. That's the one we'll, you know, endeavor to enroll in the next study. Got it. it. Thank you very much for the clarification. My last question is just regarding the concomitant atopic dermatitis patients you saw in ENIGMA 2, where you did see some sort of a clinical improvement there in those patients there with concomitant atopic. What was the clinical readout? What was the measure to assess that improvement in that population? What we used there was simply a question, I think, quote a questionnaire, but it's simply a single question for the patient to rate the severity of their atopic dermatitis daily on a scale from 0 to 10 throughout the six-month dosing period. Got it. Thank you very much for taking our questions. Sure. Thank you. There is time for only one more question. Our final question comes from the line of Patrick Trucchio with H.C. Wainwright. Thanks. Good morning. Just a first follow-up question is on EoE. I'm just wondering if you could discuss the FDA guidelines, and if it would be acceptable, if there's any reason it would be unacceptable to have the threshold of at least 24 eos per HPF built into a potential phase III protocol? Yeah, that's—I mean, I'll answer real quick, and then Craig and Evan can jump in. No, there'd be absolutely no reason, you know, as I think we've alluded to, other sponsors use 15- and 2- fields plus a previous biopsy confirming that a patient has 15 eos or higher, plus confirmation that they've tried and failed PPIs for eight weeks, you know, so on and so forth. So there are a lot of, you know, mechanisms, so to speak, that sponsors use to get the right population. So I don't see any reason why the FDA would have an issue with 24 if they don't have an issue with 15 and 2 and all those other things. But you guys wanna? Yeah, I would agree with that. I mean, I think if you look carefully at that guidance, you know, it's at a minimum having at least 15 eos per a single high-power field, but also excluding other diagnoses that could mimic EoE, in particular, looking for reflux or other things like that. So again, how you get there, I think is up to the sponsor, and certainly we will employ several measures to ensure that we really select out that population of interest. Evan, I don't know if you have any additional thoughts to that. No, totally agree. It's just, you know, you're specifying number one, they have the diagnosis of EoE, and then number two, we're looking at this more inflamed population. I agree it should be acceptable. That's helpful. Just a couple of clarification questions on atopic derm. Just the first on slide 54. I'm wondering how we should think about these data. Are those reductions in the cytokines clinically relevant, and could we expect similar declines in patients with AD? Regarding the phase II protocol, will the patients be permitted to remain on topicals, or would those be discontinued prior to their enrollment? Craig, in the AD study, are patients able to stay on topical? Yeah. Emollients, yes, but not steroids. In this particular study, we're not gonna allow topical corticosteroids, but emollients, they will be on a stable course of emollients. Sorry, Patrick, you said slide 58? Sorry, slide 54. Fifty-four. Okay, sorry. Can we just pull it back up? I didn't remember exactly what slide that was. Sorry, what was the question again? Yes. The question was just how should we think about these data? Are those reductions in the cytokines clinically relevant, and should we expect or could we expect some of the declines in patients with AD? Yeah. Whether they're clinically relevant or not, I would say yes, because these patients had chronic severe ocular inflammation. When you look at those data, and hopefully that data will be published relatively soon, you see, you know, dramatic responses on the ocular signs and symptoms, both reported by the patient, and there's, you know, really good concordance with the physician assessment as well. Then many of these patients in the conjunctivitis study also had atopic dermatitis and responded. I think the answer is yes. I mean, no one can say whether a certain reduction in any one cytokine is, quote, "clinically relevant." It has to be correlated with a clinical outcome. Certainly in these patients in this study, they had a significant clinical benefit. Yeah. That's helpful. Just on urticaria, I'm wondering how we should think about the positioning for lirentelimab and what you would need to demonstrate in phase II and phase III trials to perhaps move ahead of other biologics. You know, how should we think about the ultimate, I guess, market positioning? Yeah, you know, I guess the way we thought about it over time is, and I think the reason Marcus is, you know, so excited about it is it did appear we had activity, you know, comparable. Again, it was a phase II-A study, so I don't wanna overinterpret the data, but we did see a very nice response in the Xolair naive. Then in addition to that would be comparable to Xolair. Again, though, we're comparing apples to oranges there a little bit because of the trial sizes. Then also in the patients that were clearly Xolair refractory, we also saw a very nice response. I think, you know, data that's comparable to what we've already shown, I think would put us in a very nice competitive position. Just one last one on business development. I'm just wondering if you can discuss your latest thoughts on potential partnership for lirentelimab and/or other programs, and what the ideal composition of potential collaboration could look like. Yeah, sure. You know, again, it's probably obvious comment. We did not expect to have, you know, the negative results in these studies, but the plan was always to, you know, there's been interest in the programs over time. Our position has been to wait, you know, till post data. You know, we didn't expect to have the negative study, but I think now with the benefit of looking at the data, you know, we still. That's still the plan and, you know, we still, you know, talk to folks that have an interest in the programs, and we'll continue to do that. You know, our stated interest has been in an ex-U.S. deal, but certainly as I think we've communicated before, we don't have a religious view on that. Certainly if there's a you know a business case for a broader relationship, we'll certainly entertain that. Really what we would seek from a partner would be you know access to infrastructure and reach that allows us to do studies that we you know frankly would be hard for us to do even with additional capital you know. One of the ones that comes to mind really is asthma because those are resource intensive and typically are global studies. When you're measuring exacerbations, you're talking about a long arc of time as well. Those are the types of studies that we would be interested in you know running if we had a partner. Got it. Thank you very much. Yeah, sure. Thank you. I'll now turn the call back over to CEO Robert Alexander for any closing remarks. Well, I know we've probably run a little past, but I really appreciate everybody's attendance and questions. As always, if anything comes up, please reach out to us. We're happy to talk more about it. Thank you very much. This concludes today's conference. You may now disconnect your lines at this time. Thank you for your participation.