All right, good morning, everybody, and thank you for joining us for our first Chronic Urticaria Summit. I'm Yaron Werber from the TD Cowen biotech team, and it's really a great pleasure to have the Celldex management team that really needs no introduction. We have Anthony Marucci, President and CEO, Tibor Keler, Executive Vice President and Chief Scientific Officer, and Diane Young, SVP and Chief Medical Officer. So there's a lot to talk about, you know, as testimony of our previous session, which I think is wrapping up now with the KOLs. And with you, you are the leading sort of drug right now in efficacy, and very importantly, we're gonna see the fifty-two-week data from CSU coming up at EADV, I believe, next Wednesday. We already have the time. It's around 10:20 or so our time here, and of course, it's being presented in Amsterdam. So maybe to you, when we looked at efficacy at 12 weeks, those curves continued to get better. And one would imagine that as you continue to deplete mast cells, you'll have control of a longer-term, sort of durable control. So maybe first question is, how should we think about efficacy, and is there a chance that it's gonna get better? Yeah. Right? So, yeah, I would- I think we, you know, at the twelve-week, you know, we definitely, we had a great response, but, you know, it did look like it was decreasing, and so that's certainly, you know, one of the important things that we're, we're looking for in the data. When you look at animal models, you know, the questions we get a lot is, you know, mast cells kind of repopulated 16 weeks, but you got very nice depletion. Now, we only got data, I believe, so far, up to that 12, you know, 16 weeks, so to speak. So there could be, you know, as you continue to dose, you'll get. But is it, would you peak? And I know you can't say a lot, but biologically, do you think that one would peak at 16 weeks? Because at that way, you've already had, you know, maximal depletion, and mast cells are repopulating, albeit you're continuing to treat, or do you think that efficacy can actually continue to get down even longer? So, I'm not sure that there's a specific timing that we would expect to peak because, you know, people are different. We have a flat dosing in this study with patients of very different weights. So it's certainly possible that different people respond or achieve their maximum response at different times during the study. So I don't think we're looking at it as a specific time. We certainly believe that some individuals that don't have mast cell depletion, you know, very effectively early may develop more depletion over time. Okay. And what about safety? I think with neutropenia, we saw that patients at the lower end of normal were the ones that are kind of more likely to get neutropenic, and it looked like more of a lab abnormality. It looked like it was transient. There was no concomitant or correlation with infections, and you're already sort of getting to max depletion by 16 weeks. So would neutropenia, is it sort of a first cycle or first two or three cycle sort of effect, or does or can it get deeper with time? Yeah, so we've seen a very consistent pattern with the neutrophil counts in all our studies, you know, from the very beginning, single dose, multiple dose. You know, we see an initial decline in counts that, you know, is about the first four weeks, and then the level stabilizes, you know, and it doesn't get progressively worse with subsequent doses. And that's, you know, exactly what, you know, we predict to see in this study. And then, so, you know, while it declines to a new level, neutrophils are very variable, and so there is fluctuation. And so, you know, you may get people that transiently, you know, dip into, you know, a lower value, but, you know, it always comes back up. That's, you know, we expect to see that same pattern, you know, for fifty-two weeks as we've seen, you know, at twelve weeks. And so based on that sort of profile, as you think about a label, what would one expect, right? I imagine if there's no concomitant febrile neutropenia, and there's no infections, one wouldn't expect a black box. But what about monitoring? Is it just a baseline level, and that's it? Is it a baseline level in six months or no monitoring at all? So that's what we're thinking. I mean, when people have gone to lower levels, it's usually because they start at a lower level, and we include patients within the normal range in the study. But the people at the lower end of normal range are the ones that, you know, get the greater declines. So, I think, you know, checking counts at the beginning of therapy to know where you're at probably would be useful, and that's actually, you know, in the CSU guidelines, something that you should be doing for patients anyway, prior to treatment. So, you know, and then I think it, you know, it might depend on where you start. But, you know, most people are just within the normal range, you know, the whole time. So, I don't think, you know, I don't think it's gonna be a situation where everybody, you know, is gonna require any sort of monitoring. And then you commented, I think, when you released the CIndU data over the summer, that the rate, you said something along the lines of one in 500, and you're comfortable with sort of that rate. And obviously, we'll now see the 52-week data. As you think about that, you know, is the anaphylaxis can happen sort of any time, or is it more likely to happen sort of early on? And what can we learn from this data when we see it? Yeah, so, that's what we talked about, when we released the CIndU data, that out of 500 patients treated, we have one case of anaphylaxis. I mean, generally, if you look at, you know, anaphylaxis is something that occurs with every other biologic, virtually, and in general, it tends to be earlier in the treatment, but, you know, it can, you know, it can happen, it can happen later, but most commonly, it's early. Yeah. Yeah, we would expect it to be early, Yaron. I mean, that's historically when we look at other drugs that have been out there that have reported. They're, they're usually early. Okay, got it. And then you will also potentially have data at ACAAI in Boston, which is a month later. It's sort of almost exactly a month later. What can we see at that meeting? Is it possible to get the full CIndU data at that meeting? That's what we're hoping to have the CIndU data at that meeting. Yeah, so remember in July, Yaron, we only presented the top-line data, which was the primary endpoint of provocation test. We believe we'll have a more fuller data set in October. Right, including all the secondaries and the full safety. Correct. Yes, for the twelve-week analysis. Okay, so it'll be the full twelve-week data. And by the way, for the audience, you can see right there on the Wall Street Webcasting, there's a little box, you can ask a question there. So if you have any questions, go ahead and chime in, we can read them on your behalf, or you can just email me directly at yaron.werber@tdsecurities.com. That's our new email address. Maybe also, I wanna talk a little bit about mast cells and tryptase levels. Tryptase levels are good biomarkers. Certainly, tryptase itself comes from mast cells, and we're seeing a nice control of mast cells at the sixteen weeks, in which point they normally repopulate. Obviously, with a depleting agent, they're not gonna repopulate like that. But tryptase levels, based on the early data, they tend to recur earlier, and I think that's some of the basis about thinking about having a loading dose and hitting hard, to get to potentially boost the durability of effect and also the deepness of the effect, and maybe get to higher CR rates. You know, how convinced are you? I mean, you obviously are testing it in Phase 3, so that's gonna be a part of the dosing scheme. Some of the KOLs are saying you may translate into better effect. Some are not as convinced, right? I mean, obviously, there's no data yet. So how are you thinking about that overall? You mentioned, we believe, tryptase is a fantastic biomarker. It is correlated with the improvement in clinical symptoms in every urticaria study that we've performed. And we've been blessed to have this as a way to further provide data to support the dosing regimens that we're using. We're not just using tryptase, but certainly that is, that has proven to be a very effective biomarker. The loading doses that we've added to Phase 3 study were primarily based on the fact that we are now in SubQ dosing and using a flat dose across, as I mentioned before, you know, patients of very different size. And we expect that the loading dose will help accommodate particularly some of the larger patients early on where you really have to hit a little bit harder to take care of the mast cells and systemic KIT suppression. You know, following those initial doses, we believe a maintenance that just holds that KIT suppression where you need it to be is fine, and certainly we are extremely pleased with the data from just the 150 milligrams q4 weeks or the 300 milligrams q8 weeks without a loading dose. We've added this in as a way to potentially improve particularly for patients on the heavier side. Is there a way, you know, certainly depending on the data, to perhaps even test the q12-week dosing as maintenance? So I think, I think we have a lot of options going forward, for Phase 3 program. You know, we really wanted to use the dosing regimens that we had, you know, great data with and comfort with. I think there'll be a lot of options, whether it's through clinical development or through, you know, the clinicians' use, that may be more personalized or adjusted, in the future. But yes, we think there's a lot of opportunity to even give less frequent maintenance dosing. How would that be tested? Is that something in the OLE that you can then implement the q12-week arm, or is that something for future studies? I think it's probably for future studies. You know, we again, as Tibor said, you know, we really, you know, we in Phase 3s, we wanna really establish the safety and efficacy of these doses, which you know looks so promising in the Phase 2. But I do think that if we can get it approved and have a good safety profile, you know, the clinicians will do a lot of things to the dose as they do with Xolair today. And so would that be in? You'd probably do Phase 2 that could- No, it's possible. It could be something that would be explored, you know, in Phase 4 studies, and there's a lot of ways to look at it. We'd also want to see what the recovery rate is, you know, post treatment, Yaron. We want to see how long the response lasts after the last dose, so that's something else that we're gonna be looking into in 2025 as we see those data coming back. And that will also inform us, to your question, should we do a maintenance at every 12 weeks or what have you? So those are gonna be important data that we'll get in 2025. And just remind us, Anthony, that's gonna be when Phase 2 sort of runs out, and at that point you'll have recovery? So right now we're covering you know, we're presenting this 52-week data at EADV. Internally, we're still following those patients now that they have completed their dosing, and we're following them out now over the next 24 weeks on recovery to see how long they've maintained their response. I see. Yeah, so they were not able to continue on an OLE at that point, right? No, it's a follow-up period in the study, specifically to look at that question. Yeah. Got it. And in the Phase 3s, after the 52 weeks, they will have an option, right, either to cross over from placebo and continue on an OLE? No, in the f- In the Phase 3. No. Yeah, in the Phase 3, after the placebo-controlled period, they go on active treatment. Everybody is on active treatment. Right, right, and that's phase, 24 weeks In perpetuity. Yeah. There probably, you know, for the study, the study is studying 52 weeks, but there will most likely be, you know, an additional studies, an open label, you know, or some sort of extension study that will, you know, answer some other questions. Yeah. Okay. Got it. And at that point, if you're on the 150 mg dose Q4, you stay on 150, and if you're at 300, you stay at 300? Yes. Yeah, and the placebo then crosses over randomly to either of the two doses? Yes. Yeah. Got it. Yeah, so you'll get a preview of that with this data set, Yaron. You'll see that both the 75 milligram and the placebo groups, after 12 weeks, crossed over to get either 150 or 300 in Phase 2 study, so you'll see those data next week as well. Got it. And would you do a call on the heels of the data next week? I believe so. After the call, I'd think we would have one. Okay, so that's probably on Wednesday. It'll be on a Wednesday. Right. And I think you're also presenting some quality-of-life data, right, at EADV? Yes, it's a. We have a poster, which is, it's from the 12-week, you know, the 12-week data set that we previously presented, the primary and secondary endpoints, and we've also presented angioedema data, and now we're gonna present some quality-of-life data as well in poster. Right. Maybe let's jump into CIndU, and on the heels of the data, so we'll see the 12-week data. Maybe just remind us that the studies is continuing, right? And when we might see the follow-on data and what to expect from that program. Yeah, so what we've announced, the top line, was the 12-week analysis. In that study, patients have a placebo-controlled treatment period of 20 weeks, and then they go into follow-up, and in the follow-up phase, if they're symptomatic, they can have open-label, you know, open-label drugs. So we'll, in that study, we'll get an idea of, you know, again, how long their responses last, and also we'll get some information about, you know, retreating. And retreating? Yeah. Yeah. Option. Right, so we anticipate those data being available in 2025 as well, Yaron. Okay. Got it. Okay, and maybe just to continue the survey of the landscape, so what are the next steps on the PN program? So the PN program has the Phase 2 study, and it's enrolling, and so we're, you know, we're gonna see what that data shows. But that's, you know, that study is open and enrolling. Yeah. Yeah. Yeah. Remind us how many patients are in that study? It's 120. The primary endpoint is at 24 weeks? The primary... No, the primary endpoint is at 12 weeks, but we're looking at 12 and 24 weeks. As a secondary, yeah. Okay. Is it possible to have data next year? I know you haven't given guidance yet. It's possible next year, but you know, we'll give better guidance during our year-end call. Okay. And then the next one is that Phase 2 EoE studies is enrolling. I think on clinicaltrials.gov, there's a mention of potential data sort of around mid-next year. Mid to Q3. Yes. So we believe we'll be completed with the study we're on by the first half, and then we'll look for the appropriate medical meeting to present those data. And so probably some point in the data will be with a press release, and then maybe full data in the second half? Correct. Okay. People, you know, we get a lot of questions also on the question on in men, and going back to CSU and the Phase 2, even in CIndU, obviously, as a matter of fact, all studies, we know there is an effect on target for c-KIT inhibition on spermatogenesis. In the current studies. And there's not been any reprotox, any signs of reprotox in women, just for clarity. In the current studies, is there any monitoring for men who are participating in the studies? Not in the studies of urticaria. We have a specific study to evaluate the impact of our clinically relevant dose in healthy men. Yeah, and we're starting that study next month, Yaron. Okay. And how long is that study in terms of, duration of the treatment? So in that study, just, you know, the FDA has a guidance about what they would like to see in terms of that. And so, you know, you have to treat through two sperm production cycles, so it's gonna be, you know, about six months of treatment. And then, you know, the duration of the study will be, you know, dependent on how, you know, reversibility and how long that takes. Yeah. Okay. That'll be going on simultaneously as the Phase 3 studies will be going on. We'll get those data before the Phase 3 data. Okay. Maybe a question, in the Phase 3, I'm going back to CSU now, you're, you are looking at both sort of your... It's obviously enrolling all comers, and the primary endpoint is in all comers, but you are stratifying, and you are looking specifically at also the Xolair experience population as well. As you, you know, ultimately think about a label, you know, what, what do you think the label would look like? And then as you think about commercially, you know, how, how can you boost sort of uptake among derms, just given that derms are a little bit more finicky? So I can start with the label. What we're hoping to get is, you know, the population that's refractory to antihistamines, as well as we've sized the study to have enough data to be able to say something statistically about the omalizumab refractory population. So we would hope to have a line saying we are efficacious in omalizumab refractory subset as well. Yeah. Anthony can talk about the market. Yeah, so you're on the market. We've continued to say that we believe there are 750,000 biologically eligible patients in the U.S. and E.U. combined for this drug, I mean, for CSU patients. Where we believe that we have the advantage is that we can possibly treat all 750,000 of those patients, because some are biologically naive, some are biologically experienced, and some are biologically refractory. And our data to date has shown that we have benefited all three of those populations. Certainly, some of the other competitors out there have not shown that they would work everywhere just upfront. And then you also asked what our input would be with the derms, and I think couple of things. One, we know the derms are not using Xolair to any great extent. I mean, that, I don't think that's any big secret. But what we believe is through our clinical development of CIndU, CSU, our ongoing study in PN, and our study that will start in atopic dermatitis at the end of the year, that by the time, Barzol gets approved in CSU, we, we believe that globally, dermatologists will have a lot of experience with Barzol, and we believe that they'll be comfortable prescribing it. But, you know, that's our strategy on that. And then we know, like I said, in the US, that would be our entry point, with the derms, to use it in CSU. We know that the derms on our CSU and CIndU studies, have been very complimentary about the use of Barzol. We know in the PN study, they're all derms, and they were happy with what they saw in the Phase 1b and now with Phase 2. and then again, in AD, it's gonna be all derms there as well. So I think we'll have a lot of experience or a lot of exposure to derms and how they feel well before Barzol gets approved. And then, given the data, I wanna go back to the label, and you mentioned refractory to H1 antihistamines, and also sized to have enough data statistically about Xolair refractory patients. When we looked at all the drugs, and this is really the selling point for Barzol, it's got the best efficacy, and one would imagine the efficacy will continue to get better with 52 weeks. Is there any chance that you can also have some data in the Xolair-naive population, too? Because one would imagine the data ought to look better. Oh, yeah, I mean, we'll have data on Xolair-naive patients, and that's, you know, that would probably be a bigger group in the study than the refractory. So we'll, you know, we'll certainly be able to to have very robust data in that population. But interestingly, so far in our studies, and we've shown this, the your response seems to be the same, whether, you know, regardless of your prior omalizumab treatment. So whether you're, you know, whether you've had it and responded, whether you've had it and not responded, you know, it all looks the same, which is, that's a very, you know, unique thing about our drug. Yeah. And so you can have a statistical view as well in the Xolair naive population? I think we'll be able to do that. We're not focusing on it, but, you know, we certainly have enough patients. Great. Okay. Tibor, can we talk about EoE? I think it's gonna be sort of the next beachhead, so to speak, for KIT inhibition. And you know, EoE is called the eosinophilic, you know, esophagitis, but it looks like that might be sort of a misnomer, maybe a little bit of a marketing play for the eosinophil agents. Can you talk about the role of mast cells in EoE? Sure. So there is a number of emerging pieces of evidence that really support mast cells playing a role. They're certainly there in the inflamed tissue, and they appear to be activated, and they are... the more of them there are, you know, it seems to correlate with the disease severity. So we believe there's also, you know, strong evidence that, for example, the cytokine IL-13, which mast cells make, is one of the drivers in the disease setting. So, we agree that eosinophilic esophagitis is a misnomer, and that mast cells may be the key effector cell that's driving much of the inflammation that leads to the dysphagia. And, of course, we have the agent that can test this theory, and we're really looking forward to the data. And are there higher levels in the circulation of mast cells, or are the higher levels really in the tissue? Yeah, so they're strictly in the tissue. And not only are there higher levels of mast cells, but they are also in a more activated form, so clearly contributing to the inflammation. You mentioned IL-13, and that's a driver. Why was it called originally eosinophilic? How do we know sort of what is the real culprit here, and what's a bystander? There's clearly a lot of eosinophils associated with the disease, and it's still, from a diagnosis point of view, what is used. And, you know, they may have a role in the disease, but what's been, you know, clearly demonstrated through several drugs that do a really good job of eliminating eosinophils is that removing these cells alone is not sufficient to really impact the dysphagia and the clinical symptoms associated with the disease. Is the thinking that in the EoE study, maybe just to dive into Phase 2 design, since this really has not gotten a lot of attention, are you enrolling both biologically naive and maybe biologically sort of experienced patients? Biologically speaking, sort of what is the standard now? Is it now increasingly Dupixent or IL-5s even used there? I think, so we are, we are allowing people who have had, you know, prior therapies to, you know, and including Dupixent and, you know, study, other study therapies and things to, to enroll, provided, you know, they have to wash out of those therapies. I, you know, I don't know, Dupixent, I think, you know, is, is, is starting to be used. I, you know, we, you know, it's in this indication, it has to be given weekly. So that's, you know, that's very frequent, and it's also, you know, there's a question about who's treating these patients. You know, are gastroenterologists treating them? Are they sending them, you know, to, to other physicians to treat them? And gastroenterologists weren't generally, you know, familiar with Dupixent. So I, I don't know, Anthony, any other comments from your perspective? I think it's too early to tell the uptake of Dupixent here, Yaron. I gotta, you know, it's it hasn't been that long, and I think we just need another six months of claims data to see what it looks like. For EoE, are there any other biologics sort of used off-label even? They're not. They haven't worked, so- Yeah I don't know whether people are using them if they're approved, but, you know, they haven't worked in clinical trials. Yeah. I mean, that's one of the reasons why we're doing this study. There's just such a high unmet need here, Yaron, and, you know, we really do believe dysphagia is a big culprit here. Yeah. Well, terrific, everybody. I think we're just about time. There's also some, I believe, small groups happening, and then the next session is at 11:00 A.M. with Blueprint Medicines. So, Anthony, Diane, and Tibor, thanks so much for joining us. We appreciate it. Good to see you. Thank you, Yaron. Thank you. We always appreciate you having us on. Thank you. Great. Thank you. Thanks, everybody. Take care. Take care. Bye now.