All right, great. Let's go ahead and get started. Good afternoon, everyone. Thanks for joining us here at the Leerink Partners Global Healthcare Conference. My name is Tom Smith. I'm one of the senior biotech analysts here at Leerink. It's my pleasure to welcome our next company to the stage here, Celldex Therapeutics. Really happy to be joined by President and CEO Anthony Marucci, Chief Scientific Officer Tibor Keler, and Chief Medical Officer Diane Young. Thank you to the team for joining us. Yeah, Tom, great to be here. Anthony, I know, I think probably most in the audience are familiar with the story. Huge year of execution for you in 2024. We have some other important data sets coming up in 2025. We'll talk through some of those data sets. Maybe you could kick us off with just some introductory comments and what you guys have been up to at Celldex. Yeah, so Tom, as you can imagine, we've been very busy on the execution side. Barzolvolimab's now in five indications: chronic spontaneous urticaria, chronic inducible urticaria, prurigo nodularis, eosinophilic esophagitis, and atopic dermatitis. In addition, late last year, we commenced the healthy volunteer studies for our second program, which is our first bispecific program called CDX-622. It is a TSLP by stem cell factor bispecific that's currently in healthy volunteer studies. Obviously preparing for data sets in CSU, CIndU, eosinophilic esophagitis, CDX-622, continuing execution in our phase III studies for CSU. After we get our conversation with the FDA in alignment for CIndU, we'll start the phase III studies in CIndU for 2025. Obviously very busy, but we like the work that we're doing very much. Yep, excellent. Okay, great. I wanted to start and talk about a lot of the investor inbounds we've gotten over the last three or four months have focused on sort of competitive landscape. We've seen a lot of readouts, initial data sets, very early data sets, many of them just in healthy volunteers. There's another KIT-targeted antibody where we've actually seen some data in CSU and CIndU, a couple of small molecule KITs where we've seen primarily early healthy volunteer data. Maybe just high level, you could walk us through why you feel like your approach with Barzolvolimab antibody approach is the best approach. Just comment on, I guess, where you see Barzolvolimab position now relative to competition now that we actually have some early data points. Sure. So look, we are targeting the mast cell. And we think that that's the best way to go about it with these diseases. Certainly, Tibor can touch on it from the scientific portion of it. The data we've generated to date has been spectacular. The 52-week data that we presented on Barzolvolimab at the 150 milligram was 71% complete response rate, 76% UAS7 less than or equal to 6. And then 93% of the patients on that study had at least a 10-point reduction in their UAS7, which again, unprecedented, and only a handful that didn't have much in the way of response. It was a large data set. It was 204 patients. Like I said, the data that we put out there on an efficacy standpoint was incredible. The safety profile is as expected, transient neutropenia. We've seen some small transient or hair lightening. Later on in the study, we had a little bit of hypopigmentation, which again, once we show everybody the pictures, is benign, to say the least. We have guided that all the neutropenias that we saw on study resolved while the patients were still getting dosed on drugs. From that standpoint, we think we've hit a home run as far as efficacy and safety. The other drugs, they're very early. Still a lot of questions around them. We have a lot of questions around ourselves to ask. Certainly, what we tell people that ask us, what do you think, is we just want to see more data before we can comment. As far as the landscape goes, you have Xolair. That's the standard of care. Celltrion just got their biosimilar approved. That's going to be out there. Remi, their data looked good in phase III. I think that that will eventually get approved. You got Dupixent with their PDUFA date in April. We think it'll get approved there. We think that those are the main competitors that are out there. Where we think we will fit is basically we can go after the whole population. Realistically, the entry point is going to be post-Xolair. Based on what we see in our PN study, in our AD study, and our other studies where dermatologists will contribute in a big way, I think the comfort level around Barzolvolimab will give them the comfort to treat patients in their practices as well. Yeah. Yeah. Tibor, do you want to add anything? The only comment I would add with regards to some of the other KIT inhibitors is I think a lot of their thesis around trying to thread the needle to navigate a level of tryptase suppression or mast cell inhibition without other KIT-related side effects is really not playing out, whether it's the antibody or the small molecule approach. I think that's what we see in the data that we have so far. Anthony's correct. It's still early stage. We like the fact that Barzolvolimab is uniquely engineered. It's got the longer half-life. It's past all of the toxicology work, including reproductive toxicology that's required to support the BLA. We really feel comfortable about where Barzolvolimab is positioned. Great. Yeah, I guess we could just elaborate on that a little bit, Tibor. I guess what we've heard from some of these other companies is that kind of like threading of the needle, this idea that perhaps we can inhibit the mast cell and drive a similar level of efficacy that we've seen with Barzolvolimab without getting any of the sort of other on-target KIT-mediated side effects. I guess what's sort of your impression of that? Do you think it's possible to get that Barzolvolimab level efficacy without the same level of mast cell depletion that it is clear that you're able to mediate? I think we've been pretty consistent all along with the requirement for sustained systemic KIT suppression in order to generate the kinds of clinical benefit that we've seen. In a small proportion of patients, that may come along with some tolerability issues around hair color changes, and a small subset may develop, after a long period of time, some skin hypopigmentation. These, according to our patients, are a great trade-off for the kind of clinical benefit that they're seeing. I think that's what we have said from the beginning. I think the data that's coming out is continuing to support that even with other drugs. Of course, you've seen the pictures with the hair color changes and the hypopigmentation. They're minimal, right? I think, in these kinds of diseases, pictures are worth a thousand words. As long as we show them, people are like, yeah, this is not a big deal whatsoever. We know that completing 52 weeks of dosing, we've talked to patients about how they feel, how they tolerate it. It's everything that we expected. Yeah, that makes sense. I guess, I mean, the way I think about your clinical data set, we have two large phase II studies. We have the CSU data and out to 52 weeks. Within the context of that, I like to think of it with three quarters of the patients treated throughout the study, roughly 70% of those, almost three quarters of those patients achieved complete response, unprecedented levels of efficacy. You just presented some updated data at Quad AI focused on more of the quality-of-life metrics. Could you just kind of walk us through some of the highlights there and how that builds on what we already saw out of the urticaria disease activity score data from last year? Yeah, so we had two posters at Quad AI, both on quality of life. One was from the CSU study, the 52-week data. We looked at both the Urticaria Control Test and we looked at the DLQI. In both cases, the patients really started the study with quite impaired status. I mean, their UCT showed very poor control. Their DLQI showed that their disease was having a very large impact on their lives. By the end of 52 weeks, we had about 80% for each of them showing well-controlled urticaria and showing that their disease had minimal or no impact on their quality of life. Those are some of the best results seen with quality of life and go very well with the symptom reduction. The other poster that we had was in the CIndU population. That was the 12-week data. The same thing, we looked at both UCT and DLQI and had very nice improvements in both of those at 12 weeks going along with the negative provocation test that we saw in the earlier presentations. Yeah, that's great. I mean, I thought from the DLQI data, nearly every patient experienced clinically meaningful improvement. Correct. When you take the minimal clinical important difference, it was like 90-plus%. Yeah, which correlates well with the response. Quite striking. Yep. Okay, great. And we, later this year, we're expecting even longer-term follow-up from both studies. Maybe just help frame expectations. What can we expect to see there? I know the CSU study is 76-week data. It's, what is that, 24 weeks off of treatment? What are we looking for specifically with that data set? What we're looking for is to follow those patients out, obviously. We want to see how many of the patients' disease came back, how many of the patients had well-controlled disease, a complete response, a change. We want to see how the safety looks. This will be the first study that's ever shown this kind of work being done. We also want to look and see at the end of the day how many of those patients maintained benefit. Because we know that based on some meta-analyses that are out there, the spontaneous remission rate for CSU patients is about 10%-12%. When I look at these meta-analyses, they're taking things from different studies. When we asked our KOLs and PIs, what are they seeing historically as a spontaneous remission, they're saying about 10%. We have an opportunity here to follow these patients out another 24 to 28 weeks. When we take a look at that data, we'll see how well that they are doing. I think that that's important because in the real world, patients aren't treated forever. They're treated for a certain period of time. They get the patients under control. Then they give them what they call a drug holiday. This will fall under that parameter for us. Like, okay, if we give it three, four, five, six, seven, a year, what kind of benefit are they seeing? What can we expect to additional benefit going over? That's going to be really important to us as far as the 76-week data. Got it. It sounds like on the basis of some of those benchmarks, you think 10%-12% spontaneous remission rate, what would you see, I guess, as perhaps maybe a little bit more of like a clear signal above that that would indicate to you that you are having maybe a little bit of a remitted effect? Yeah, so we've asked the KOLs. And they say if you can get anything above 12%, 15%, 18%, you're good. When we ask investors, it's a little bit more aggressive, 20%, 25%. But we'll see. This is a large data set. It should give us a great signal. And we look forward to presenting it. That's great. Yeah. Just in terms of, I guess, durability of efficacy and maybe some of what we've also seen in some of these competitor data sets, I mean, it does appear with their dosing intervals, they're unlikely to get the same level of mast cell depletion or even suppression as what you're achieving. Even in the cases where they are able to achieve a complete response for some period of time, it seems like that response may wane rather quickly. I guess just help us think through kind of the mast cell kinetics. Just, I guess, conceptually, when you think about a remitted effect, what is actually driving that, do you think, in the urticaria patients? Yeah, so we know from our data in CIndU patients that mast cells actually repopulate relatively quickly within weeks of the drug clearing and stopping KIT suppression. When they come back, patients with CIndU responded to the provocation testing again. A short duration of mast cell depletion does not change the picture very much. The question we are trying to address and that we are really interested in is when you have sustained mast cell depletion, mast cell suppression in these urticaria patients where we do not fully understand the pathophysiology of the disease, are we able to drive some of those patients into sustained remission, much like the spontaneous remission, by resetting sort of their immune system, their mast cells to that? Certainly with 52 weeks of treatment, there will be an additional number of weeks of exposure as the drug clears. With the 24-week follow-up, they will certainly be without a systemic KIT suppression for some period of time. We'll see tryptase levels come back. I'm confident of that. We will look to see how their disease responds at that point. Got it. That makes sense. On the CIndU side, we're also looking for follow-up data. Any differences that you would call out in terms of what you're looking for there? Similarly, with the CIndU study, we have a 20-week placebo-controlled period. They actually go to follow-up, although we have an open-label extension so that presumably patients who are on placebo or something can start drug. Others, if their symptoms come back, can start drug. That will be a little bit different data. Yeah, we are going to look to see how long those responses are sustained. Also, we can look for reversibility of the KIT-mediated adverse events, the hair color change. We see that those are reversing. This will give us time off drug to show. We will also see that those patients that have come back on, did they respond again? That will be another key point to look at. Right. Okay. Interesting. Just timing, I guess, in terms of both of those, could we see both of those simultaneously? Is there anything more precise we can say on timing? Q1, I'm sorry, first half for the 76-week data, second half for the 44-week CIndU data. Great. Okay. I want to talk a little bit about the phase III EMBARQ program. Maybe you could start, just provide an update on how enrollment's going and how you're thinking about it. I think you've kind of historically said two years probably to enroll. What are the early trends suggesting? What's the level of confidence in that two-year time frame? Is there potential to maybe accelerate it even? Yeah, good try, Tom. It's the crew, and as expected, we're very happy where we are. We did guide to two years when we first started it. We're very happy where we are. It's in 460 centers around the world. We're in 40 different countries. Remember, it's two phase III studies of 915 patients each. They're identical phase IIIs. We're just looking forward to accruing it and eventually getting the data out there now. That's great. One of the changes, obviously, from the phase II experience is the introduction of the loading dose. I guess, what are the expectations, both in terms of, I guess, rapidity of onset, but also any other safety considerations? Yeah, so we think that the data have suggested that by giving a loading dose, we might have a more rapid response to getting the mast cells down to a depleted level faster. In terms of additional safety issues, these doses are well within what we've studied throughout the program. In this range of KIT suppression, we don't really see differences between the doses. We think that the profile will be similar. Did you have anything to? Just to remind folks that with the flat dosing and you're trying to cover a very large range of size of patients, we also feel the loading dose will help with particularly patients who are heavier who could benefit from a larger dose in the beginning. Yeah. Remember, we had patients that were in that 150-160 kilo range. Those are large numbers. Yep, that makes sense. Okay. Phase III CIndU, you're expecting to engage FDA. I guess, what's the latest thinking around that potential timeline to kicking off a phase III program there? Yeah, so we've said we want to start phase III by the end of the year. What we need to do is have a meeting with FDA. That's really to align around the endpoints that we're going to use in the study as well as defining the patient population. There is nothing approved in CIndU. We want to get alignment on that. The data is going to be related to patient-reported outcomes. We need to understand that we have sufficient validation of the outcomes and things liaake that. We're planning to have that meeting and then start the phase III by the end of the year. Those studies will be much smaller than the CSU study. The CSU study, since it's our primary and our first indication, that will be the one that has the large safety database. We've also sized that study. We would say something statistically around not only the naive population, but the experienced and the refractory population in CSU. Those are the reasons why those studies are so big. The rest of the studies, whether it be CIndU, EoE, PN, and AD, should be somewhat much smaller as we go through. Got it. That makes a lot of sense. Maybe just lastly on urticaria, I know you've done a lot of work analyzing claims data and taking a look and trying to triangulate exactly what you think the commercial opportunity looks like in terms of number of patients in both CSU and CIndU. Maybe just what's the latest thinking in terms of addressable population proposal there? Yeah, so the addressable population for me was always 750,000 between the U.S. and Europe that were biologically eligible. Novartis has come out with numbers that are logs larger. I mean, they're estimating anywhere between, I think, 3.7 and 4.2 million. The question is, are those all biologically eligible patients? As you know, our studies have always been around the moderate to severe patient population. Until I can see otherwise, I would imagine maybe it's larger than what I'm suggesting. If it's 4 million plus, then I got to redo my model because it's really conservative. Okay. That's great. Let's shift gears and talk about EoE. This is an important proof of concept readout we have coming up in the second half of the year. I know you guys, you've made some changes in the study kind of mid-course. I think we introduced a loading dose here. We changed the dosing interval. We just changed the dosing interval. We changed the dosing interval. In that backdrop, maybe just help frame expectations, what you're looking for, like what you would consider success in this phase III proof of concept study. Yeah, we did increase the dose. That was based on seeing data from our other studies regarding the safety profile and understanding that different doses may be needed for different diseases. The one that stood out to us so far was the early PN study where 3 milligrams per kilogram was better than 1.5 milligrams per kilogram in that population, whereas they were the same in chronic urticarias. We increased the dose to 300 milligrams every four weeks instead of every eight weeks. We really just were only looking at one dose level. We wanted to maximize our chance for success. In terms of our efficacy readout, our primary endpoint is the number of mast cells per high-powered field. We made that our primary endpoint because we know that we should deplete mast cells. We think that we will deplete eosinophils as well, but we don't know how much. Of course, eosinophil counts is the endpoint that FDA has in their 2018 guidance as well as Dysphagia Symptom Questionnaire. All of our secondary endpoints in the study are those classic endpoints that Dupixent got approved on. Everybody else has gotten histologic remission but not symptom control and therefore did not succeed. We are going to be looking at all those. What we say at this stage is we want to be at least as good as, if not better than, Dupixent, which is the one approved agent. Right. Do Do you want to answer? No? Okay. Yeah. I mean, this is probably among the most egregious misnomers in all of disease states. The guidance as it sits today is kind of the guidance as it sits. It is what it is. I guess in your engagements with the agency, I don't know the last time you engaged them around EoE. Do you have a sense that there may be a path forward that uses mast cell depletion as an endpoint here in the same way that eosinophil reduction is used as an endpoint? I know some of the others that have attempted development work in this space have talked about going after, I think it's called MGID, but basically mast cell-driven GI disease, although there wasn't an established regulatory path. What's your sense of regulatory flexibility kind of where we sit today? I think given that there's been so many failures using the endpoints that they established, and I think if we have good symptom relief, I think they will be open to considering other endpoints. I think they're very science-driven ultimately. And if we have the data, we'll be able to talk to them about it. Yeah. If we also have an impact on eosinophils, it fits their narrative as well. Right. No, that makes sense. Just biologically, what's driving the impact on eosinophils? We know we're not directly depleting eosinophils, but it's more of a recruitment. Is that right, Tibor? Yeah, I think there's recruitment. There is activation involved. We know that mast cells and eosinophils form an allergic unit. They can perpetuate each other in a way, mast cells being the tissue resident cell that really secretes a lot of molecules that drive eosinophils, but also TH2 cytokines like IL-13 is a major source from mast cells. Again, we would be expecting to see that mast cell depletion has an impact in this disease. Have you looked at that, I guess, in any of the other disease states via biopsy, for example, in CSU? Or do we have preclinical data that gives you maybe a certain level of confidence that we'll see that in EoE? We have documented in CIndU biopsies that we deplete skin mast cells. We have looked at that both by immunohistochemistry and by RNA sequencing. The mast cell signature goes away rapidly. It actually comes back also rapidly, with tryptase in the serum coming back. We have not looked specifically yet at cytokines and other molecules. That is something we are going to have a lot of data from the EoE study. The biopsies, as you know, are part of the analysis for these patients. We will be doing extensive work on looking at all the activities associated with treatment with response. Yeah, that makes sense. This is top-line data in the second half of the year. I guess any more precision on? We'll have the full data set in the second half of the year for the EoE also. Okay. Okay, great. Yeah, we don't want to do top-line and then pull out the full. We'll pull out the full data set in one shot. Okay. That makes sense. Let's shift gears and talk about atopic dermatitis. Most recently started program. I guess my sense of kind of where investors are today, a lot of the inbound questions are around how are we controlling placebo response? For example, we've seen a number of, I guess, the last three phase II readouts have been fairly challenging in terms of outsized placebo response. Maybe you could just talk about, I guess, how you designed the study, maybe some of the quality control aspects that you've implemented, and how you guys are thinking about a top-line readout. Yeah, we discussed with the experts in the field about some of the recent failures and the idea being that you're getting too many milder patients. We've tried to keep our inclusion-exclusion criteria to have a more moderate to severe population. We're going to be following very closely to make sure that patients are meeting those criteria. We see our sweet spot being post-Dupi or IL-13, but prior to the JAK inhibitors. We know that most of the study is going to be those patients that have either failed an IL-13 or a Dupi or even a JAK and then get on our study. In theory, those patients are going to be a little bit more severe, a little bit more tested with drugs. The rationale is that maybe that helps with the high placebo rate there too. That makes sense. Okay. Just in the last couple of minutes we have, I want to touch on the CDX-622 program. And this is your TSLP stem cell factor bispecific. Maybe Tibor, if you just elaborate a little bit on why targeting stem cell factor here and then I guess what you hope to gain in targeting both via multi-specific antibody. Yeah, so we really want to build off the success we're having with Barzolvolimab. In the context of bispecifics, we thought we'd go after the ligand of KIT, stem cell factor, that prevents any concerns with cross-linking KIT inadvertently. We also think targeting stem cell factor is really interesting because it comes in two forms, a soluble form and a membrane form. We can look at the effect of targeting predominantly the soluble form, which is the antibody that we've developed here, which may have a differential effect on mast cells than other KIT processes. Of course, we're combining that with a now well-validated TH2 barrier disruption pathway. We think there are many disease opportunities for that. Got it. That makes sense. We are looking for healthy volunteer data from the single-dose portion of that later this year. Just help kind of frame expectations, like what would be an encouraging readout there for you? I think for bispecific antibodies, a lot of the challenges relate to the pharmacokinetics, to the immunogenicity just based on the type of molecule. In this case, tryptase is our readout for the stem cell factor side of the molecule. We'll hopefully also get some good TSLP engagement data and the safety profile clearly in terms of hematologic effects, in terms of other KIT-related adverse effects. It will all be really interesting. Unfortunately, we're up against time. I want to thank the Celldex team for joining us and providing the updates. We'll stay tuned. A lot of data coming this year. Thank you, Tom. Appreciate it.