All right. Good afternoon, everyone. Thanks for joining us here at the SVB Leerink Global Healthcare Conference. My name is Tom Smith. I'm a senior biotech analyst here at SVB Leerink, and happy to be hosting this next fireside chat with Celldex Therapeutics, where we're joined by CEO Anthony Marucci, CSO Tibor Keler, and CMO Diane Young. Thank you all for joining us. Yeah. Good afternoon, Tom. Just one quick housekeeping note here before we get started. For investors joining us on the webcast, feel free to submit any questions for the Celldex team in the webcast portal or email them to me directly at thomas.smith@svbleerink.com. With that, Anthony, it would be great if you could kick us off with just a brief overview of the company for those in the audience who may be less familiar with the story. Yeah, happy to, Tom. Before we do that, obviously, I need to make the disclosure that to the audience today that we will be making some forward-looking statements and that we would refer everyone to our SEC filings where we discuss those in more detail. For those of the people on the call that are less familiar with us, you know, we are a publicly traded immunotherapy company. Our focus historically has been on human monoclonal antibodies and bispecific development. Therapeutic areas that we work in are in the immunoinflammatory space as well as the immuno-oncology. You know, our recent data over the last year has been focused on the CDX-0159 program, where we've had some excellent data in chronic inducible urticaria, and we're looking forward to our phase I-B data in chronic spontaneous urticaria later this year. Certainly, the pipeline is expanding now. Late last year, we entered into our third indication in prurigo nodularis. On our year-end call, which we believe is gonna be on February 28 after the market close, we'll talk about our fourth indication as well as some subcutaneous healthy volunteer data that we have to discuss. The company's well-capitalized. We had several raises in 2020 and again in 2021, so we feel that we have enough cash to get us through 2025 and to complete all the clinical trials that we will be working on this year. 2022 is obviously gonna be a very busy year for us, not only starting phase II studies and additional phase I-Bs, but also getting data from our phase I-B in CSU, which we hope to present at EAACI later on this year. That's the quick rundown. Okay. Perfect. Yeah. Great overview and yeah, certainly a number of upcoming data points I know investors are gonna be keenly tuned into. I wanna start with a little bit of background on CDX-0159. Maybe if you could just walk through a little bit of the development history here. We know you had a predecessor compound, CDX-0158. Can you talk about you know some of the work that was done I guess with the predecessor compound and then some of the changes that you made to end up with 0159 to push that forward in autoimmune disease? Sure. Yeah. I can take that. CDX-0158 is a molecule or an antibody that we acquired with the acquisition of Kolltan Pharmaceuticals, and it was discovered there that it was a highly potent inhibitor of KIT signaling. KIT is obviously a very important molecule for mast cell survival and function. That particular antibody was investigated in a phase I trial of GIST cancer patients in a dose escalation study. That study did not demonstrate any clinical benefit, unfortunately, and at least our interpretation, there is because the mutations in the KIT receptor that are commonly expressed in GIST tumors often induce the internalization of that receptor, and it no longer requires stem cell factor interaction to drive KIT signaling. What we did subsequent to that study to help improve CDX-0158, because one of the other outcomes in the study was to recognize, you know, severe infusion reactions that were occurring and what we believe is through mast cell degranulation occurring through the Fc domain of the antibody interacting with Fc receptors on the mast cells. We did some engineering. One set of mutations was engineered into the Fc domain to eliminate binding to Fc gamma receptors and prevent that or greatly reduce the ability to activate mast cell degranulation. At the same time, we introduced additional mutations that would improve the relatively poor half-life that was observed with CDX-0158. That's essentially what we've done with CDX-0159. Of course, the clinical studies have borne out that those mutations actually had the impact that we wanted. Okay. Yeah. Great. That's helpful to see where. I guess just thinking about it, I mean, you mentioned some of the impacts of KIT inhibition. I mean, we know on target, you know, impacts for spermatogenesis, impacts hair color, impacts hematopoiesis. I guess, you know, if you could just walk through some of the changes that you've seen clinically and then also, I mean, one of the other questions I hear frequently from folks, specifically as it relates to this for spermatogenesis, is just around some of the preclinical work that you're doing to characterize some of that repro tox. Just what's the latest in terms of where you are with the preclinical studies? Sure. Well, we have observed some effects of KIT inhibition on other cells. We see obviously a small impact on hematopoiesis, which has not shown to be clinically significant. We have had some patients comment on some lightening of hair in certain patches. This has been well described for other KIT inhibitors. Overall, we don't think what we've observed so far is in any way clinically limiting our development. From a preclinical perspective, we are conducting a number of studies. Currently doing the six-month chronic toxicology study, which is required to support our phase II trials. That is being done in mature animals, which will give us an opportunity to assess some effects on reproductive toxicology, including spermatogenesis. We'll be having some of that data this year. Additional reproductive toxicology, as you know required by FDA guidelines, will be performed over the next couple of years to you know further support and identify any potential hazards. Okay. We should expect an update and I guess visibility into kind of the progress within those studies at some point in 2022? Is it fair to say kind of mid 2022? Help us understand just timing-wise. Well, certainly the analysis from the six-month chronic tox study is required to support the longer term dosing in our phase II trials, which we anticipate initiating in the first half of this year. There will be at least visibility into the ability of us to move forward into those studies. With that, these studies also involve a longer term follow-up, what's called recovery period, for any findings that you see to determine whether or not they are reversible. Based on all the information and biology that's been reported on these potential mechanisms, we certainly expect any findings we have to be fully reversible. That data won't come till later this year. Okay. Understood. Yeah, that's helpful. Then just maybe lastly on the mechanism, I mean, and I'm asked this frequently from investors as well. Just help put CDX-0159 into context versus some of the other CD117 targeted antibodies in the clinic from the likes of Jasper and Magenta. Yeah. As you said, I think they're quite different in their approach. They are going after the ability as a conditioning agent, where their intention is actually to deplete stem cells. The Magenta antibody, as I understand, is an antibody-drug conjugate where they're delivering a toxin and is very effective at depleting stem cells. In the case of Jasper, is more similar to the Celldex approach with an antibody that targets the stem cell factor binding area on the KIT receptor and is very potent at blocking that receptor. We don't understand fully why they see greater effects on hematopoiesis than we've observed with 0159, but it could be nuances in terms of the mechanism between these two antibodies. Okay. Okay, that's helpful. Maybe we can turn to some of the exciting clinical data that you've generated in inducible urticaria. I mean, this follows, you know, dose ranging in healthy volunteers, single ascending dose in healthy volunteers. But the data that you reported last year in inducible urticaria, extremely impressive efficacy. Maybe you could just walk us through kind of the high level results there and how they compare versus, you know, pretty much any of the other inducible urticaria datasets or urticaria in general datasets that we've seen to date. Sure. In the study that was presented last summer, it's a study in inducible urticaria, looking at the two most common forms of inducible urticaria, which are cold contact urticaria and symptomatic dermographism. In that study, we gave the patients a single dose of CDX-0159 at 3 mg/kg. We measured the response by the ability to induce hives with provocation tests. There's something called the TempTest which we used for cold urticaria and the FricTest for symptomatic dermographism. We saw that with just the single dose we had 100% of the patients had a response, and 95% of the patients had complete response, meaning that you could not induce their hives with those tools. The responses were very rapid. They occurred, you know, within one to four weeks for most patients, and they were also durable. They lasted throughout most of the 12-week follow-up period. In addition to those provocation tests, we looked at some measures of the patient's quality of life and their urticaria control, and those also reduced. Very importantly, we have a biomarker which is tryptase, which is thought to reflect mast cell burden in the body. We saw profound reductions in tryptase as we had in our healthy volunteer study. We saw in skin biopsies that we depleted mast cells. It was very exciting to see this whole proof of principle, and everything kind of come together in the one study. I would say comparing it to other agents there, you know, there are no approved agents in CIndU beyond antihistamines. There had been some pilot studies with XOLAIR in symptomatic dermographism and cold contact urticaria. They were done basically at the same center that we did our study with the same tools. In those cases, they showed some more like a 50% complete response rate in terms of the provocation tests. It took longer to get there. You know, they were measuring the response at 10 weeks instead, you know, rapidly as we saw. There was also some early data with the Allakos compound in symptomatic dermographism. On their prick test results, they had about a 50% response rate. You know, really great response rate in that study. Yeah. No, it certainly helps put it into context. Really stellar efficacy results. I guess, as we think through, kind of the pathophysiology here and the pathogenesis of, you know, of urticaria. I mean, is there any mechanistic reason or other rationale for thinking that the inducible urticaria results wouldn't translate into chronic spontaneous urticaria? No. Well, we think that all urticarias with the mast cell is really the primary cell driving it. There can be some individual differences in the disease. One difference between spontaneous and inducible urticaria is that for inducible we had the FricT est and the TempTest, which you actually induce the hives, and it's kind of an objective measure. Chronic spontaneous urticaria can kind of wax and wane a bit. So there's some level of patients improving or getting worse on their own. The other thing is that the endpoint that we're measuring for chronic spontaneous urticaria is a patient-reported outcome tool. It's the Urticaria Activity Score. Often with tools where patients are reporting, there is more variability. We do, you know, we do expect that we will have in the chronic spontaneous urticaria as well. Okay. I guess, thinking to kind of the safety tolerability side of the equation, you know, within the CSU data set, you are doing some dose ranging. This is also your first, you know, multi-dose data set for CDX-0 159. Is there any reason to be concerned, I guess, by the mild and the transient asymptomatic decreases that you saw in hemoglobin and white blood cell parameters from the CIndU study or from the healthy volunteers? Well, as Tibor mentioned, you know, we're following hematology very closely because it is, you know, a target of KIT, the hematopoietic stem cell. That being said, so far, you know, everything has been mild and nothing clinically significant. We believe that we are, you know, saturating at the doses that we're at and that that's persisting for a long time. We don't think that subsequent doses are going to make anything worse in terms of any observation of hematologic parameters. We have some evidence of that, both in our chronic tox studies, where we did not see, you know, progressive worsening of any hematologic parameters, and also from the CDX-0158 that Tibor described earlier, where we did treat patients every three weeks for doses up to 15 mg/kg. And were able to deliver multiple cycles, including one patient that went out to two years and didn't have, you know, progressive hematologic issues. Okay. It's the combination of, you know, what you've seen pre-clinically meets, I guess, the experience with CDX-0158, where you did have at least one patient that was dosed out pretty long duration of dosing. If I recall correctly, at a pretty high dose relative to what you're exploring for CDX-0159. Yeah. I guess it's kind of difficult to compare data sets there in the sense that CDX-0158 was in a GIST patient population, oncology patient population. Did you see? I mean, I guess across kind of any of the patients enrolled in those studies, like were there clinically relevant changes in heme parameters that were deemed possibly related to drug? There was nothing, you know, clinically significant. You know, as you mentioned, being GIST patients, they may have had other therapies that may have compromised their bone marrow a bit. You know, we definitely did not see any, you know, clear signal of anything, you know, due to chronic dosing in that study related to hematologic parameters. Okay. Appreciate that. We do have an inbound question here from an investor. I'm gonna paraphrase a little bit, but basically just asking Tibor if you could elaborate a bit on the differences between CDX-0159 and the Jasper compound, and why there might be a difference in stem cell depletion or hematologic tox based on what's known between the two compounds. Yeah. Well, we don't have any definitive data. What we know is that the mechanism by which they inhibit KIT signaling is slightly different. The Jasper antibody, as I mentioned, binds to the KIT receptor at the same place that stem cell factor binds, and that's its mechanism of blocking stem cell factor mediated signaling. There's a unique mechanism around CDX-0159 that binds to the KIT receptor in a way to prevent its dimerization. Therefore, KIT, a stem cell factor has real significant issues with being able to bind, because stem cell factor needs to dimerize itself in order to be able to bind to two KIT receptors and induce the signaling. There are differences by which these antibodies work that may be partially responsible for differences that we're observing in regards to effects on bone marrow. Okay. Yeah, that's helpful. I wanna turn to, I guess, expectations for the upcoming data at EAACI. You've mentioned, I mean, you now have a cholinergic inducible urticaria cohort. I think we're also expecting that at EAACI, but it seems clear to me that the focus will be on the multi-dose CSU data. What are your expectations? I guess help investors kinda think about where expectations should be ahead of that data set. We said that we're, you know, planning to submit data to EAACI. We haven't really guided about the details, but we're planning to present as, you know, robust a data set as possible. Okay. Can we talk a little bit about one of the surprising developments in the urticaria field, you know, over the last six months or so was the failure of Novartis' ligelizumab. Maybe if you could talk a little bit about the approach there and it's speculation, right? We haven't seen the details, but where you think ligelizumab may have fell down in terms of efficacy. It's hard to say because you know, we haven't seen the data. You know, I think that study was set up so that their success criteria was that ligelizumab had to do better than XOLAIR. From what we understand, it did do better than placebo, but they had actually set the study up based on a phase II study and selected their dose, you know, based on trying to pick something that would be better than XOLAIR. I think we're really interested to see the data and see what happened there. You know, was it something about the you know, the patient population? You know, what went on? You know, I think that's the main thing that we're interested in. I mean, they have said they're gonna, you know, show the data later in the year, so we can have a look at it. Yep. Okay. Yeah, we'll certainly be on the lookout for that. I wanna talk a little bit about CDX-0159 in prurigo nodularis, which is the most recent indication expansion, and you know kicked off a study there. I guess kinda walk us through the rationale, like why prurigo nodularis as the next indication up and you know talk about I guess what we can expect to see from the proof of concept study, and any sense of timing in terms of data. Yeah. Prurigo nodularis came out of a similar process to what we've gone through with all our indications, which is that we do this very in-depth analysis and we look at the data about whether mast cells are implicated in the disease. Is it an unmet medical need? Is there a regulatory path that we can foresee? The commercial potential. You know, prurigo nodularis, there's some interesting recent data suggesting that mast cells and sensory neurons interact to the really severe itch that's associated with prurigo nodularis. This was really interesting to us to pursue. It is an unmet medical need. There's nothing approved for it. It's really a devastating disease. The other thing that we liked about it was that, if we can show that we reduce itch and heal lesions of prurigo nodularis, we have the potential to go after, other diseases where neuroinflammation is, you know, is an important mechanism. That led us to start our study, which initiated in December. The study is a placebo-controlled study looking at, you know, three doses of CDX-0159. We were really looking at itch as the primary endpoint with the worst itch scale. We're also looking at the healed lesions, which takes longer than itch because a lot of healing has to go on. You know, we haven't really definitely decided when we're going to present, but we would really hope to have some results by the end of the year. Okay. No, that's great. Let's talk a little bit about kinda next steps for CDX-0159. Anthony, you alluded to you know, naming another indication here in the relative near term. I guess strategically, help us understand how you think about the indication expansion. I mean, you're thinking about kind of the broad spectrum of mast cell-driven diseases. Yeah. What goes into that evaluation process, just help us think through kind of the strategic evaluation. Yeah. I think Diane has touched on it already. I mean, we look at three buckets, the science, the clinical abilities, and then the commercial opportunities. We're looking at unmet need, we're looking at the role of the mast cell, whether it plays a contributory or a vital role in the disease. Then we're looking at feasibility in conducting clinical trials as well as what's the possibility of success in those trials. Then lastly, we look at the market opportunity around that, and collectively we score them and we make a decision to move forward. CSU obviously it met the high unmet need, it met the mechanism of action, there's feasibility to do the studies and, you know, so far so good with the probability of success. We've been successful in the CIndU, and then we think that the market is there. The same thing with PN. We think the market is a bit smaller, but it could be larger as you expand the ability to treat patients with a biologic. The next indication will be the same thing. That's how we look at them in general. Okay, great. Yeah, that's helpful. I also wanna ask about how you're thinking about the dosing going forward. Obviously the CSU study is, you know, doing some dose ranging. You're looking at Q4 week and Q8 week dosing. You also recently added a cohort to the CIndU study, looking at single doses of 1.5 mg/ kg. Just how are you thinking about dose evaluation here? Is there any possibility of exploring even less frequent dosing, perhaps Q12-week dosing intervals? Yeah. I guess the most important thing is that we're, you know, we're planning to move to subcutaneous dosing in the future. We do have a healthy volunteer subcutaneous dosing study that we will be reporting on at our upcoming call. I think it's very nice that we also have tryptase as a biomarker, so that's gonna help us look and compare, you know, what we've seen with intravenous dosing and subcutaneous dosing. Right now we're thinking that for the urticaria studies that we're planning, we are gonna have to do dose ranging in phase II. We're going to look at several doses and schedules. We're trying to find, you know, a dosing schedule that will, you know, allow the patients to have, you know, control their urticaria over the whole dosing period, but also be, you know, spaced as conveniently as possible to the patients. Whether we can go to 12-week dosing, it's also a function of how high a dose we could give because with subcutaneous dosing, you don't wanna have to give too much of a volume to the patient, because that would be uncomfortable. We're putting all those things together as we gather the data. We do expect to be able to dose, given the long half-life that we have, we, you know, expect that we're at least at a minimum, gonna be every month or, you know, every eight weeks. Okay. Yeah, that's great. Yeah, we'll be tuned in for the initial healthy volunteer data for the subcutaneous dosing. Can you just remind us on the, I guess the formulation there, how is it formulated, the concentration? It's formulated at 150 mg/ ml. Okay, just remind us how you're planning to incorporate the subcutaneous formulation into the broader clinical program? We're gonna start using the subcutaneous formulation in our phase II studies. We envision that for most of the indications we're looking at, the subcutaneous dosing will be the preferred method, so we're gonna start incorporating it. Okay. Maybe just in the, I know we're up against time a little bit, but I did want to touch on the oncology program. Maybe just a brief update on the oncology assets, CDX-1140, and, you know, when we can expect to see the next data update there. Go ahead. Yeah. CDX-1140, it's in the phase I study. We're currently doing cohorts in combination with pembrolizumab, and we reported in November, we have some encouraging early data in head and neck cancer. Right now we're waiting to accrue those cohorts, and then we'll present that data. Okay. Excellent. That is, this year? Update probably maybe second half? Well, yeah, it would definitely be in the second half. Okay. Understood. All right, guys. Well, unfortunately, we're up against time, but really appreciate you joining us. Thank you for the updates and the insights, and thank you to the audience as well for joining us, and we'll stay tuned. Certainly a number of exciting data points on the very near-term horizon. Yeah. Great, Tom. Thank you for having us. We appreciate it. Thank you.