All right, good afternoon, everybody, and thanks once again for joining us for the 45th Annual TD Cowen Healthcare Conference. I'm Yaron Werber, along with my colleague Jane Hun from the biotech team, and it's a great pleasure to moderate the next fireside chat with Celldex. This is very timely, coming freshly off the Quad AI Conference, you know, literally this past weekend. To my left is Tony Marucci, President and CEO. To his left is Diane Young, Chief Medical Officer, and to her left is Tibor Keler, Chief Scientific Officer. Ladies and gentlemen, thank you for joining us.
Thank you.
Appreciate it.
Thank you for having us, Yaron. Good seeing you again.
Lots of questions. I'm going to start with the phase II CSU data. The next data, so far we've seen the 52-week data. The next data cut that I think we're going to see is 76-week data. If I recall correctly, the way the phase II ran is patients who are on drug for a year, and then there's a treatment-free period for 24 weeks, i.e., 76 weeks, which was going to look at potential for remissive durability of response and obviously, you know, tolerability and things like that. I guess the first question is, what should we expect from the data? I think we know a lot about safety already, but maybe even more so on efficacy and durability. Secondly, when could we see the next cut?
Yeah, so as you say, it's the 76-week data. We had a 52-week treatment period, and the last treatment was given at 48 weeks. What it's going to show is, you know, as you all know, during the 52 weeks, we had a very high complete response rate, and it's going to show what happens to those patients off drugs. How long does their response last? It also gives us the opportunity to look at adverse events, particularly reversibility of adverse events off drug.
We're looking to see, in part, how long the patient remains in remission or benefits from the drug, and also take a look at the safety parameters.
We know that, right, mast cells do not really come back for about 16 weeks, but they start, you know, sort of coming back. At least that is a life, you know, an average of a mast cell, so to speak. You would expect that the effect at some point is going to start wearing off, probably gradually over time. What sort of a good, what should we hope to see from the data? What is considered good data? I mean, you know, biologics usually are treated chronically, right? They are not treated for a treatment-free period.
Yeah, I would start by challenging the 16-week number a little bit, particularly when the mast cell numbers are suppressed using anti-KIT therapy. What we've seen is actually tryptase levels come back in a number of weeks, and we think that's reflective of repopulation of the mast cells. This is a really interesting experiment. We have suppressed mast cells substantially in these patients for a year. You know, we're really asking the question that as the drug mitigates over time, we think that's going to take, you know, maybe even a couple of months for the drug to clear from the 48-week time point, but these patients will have, you know, still be a number of months from reaching the 76 weeks where they will no longer be on KIT suppression whatsoever.
It is in that time period that is going to be really important to understand, are we resetting these patients in terms of their mast cells and their sensitivity to some of the triggers that cause this disease where we do not fully understand the pathophysiology? That option, you know, really talks about disease modification, and that is something we are really interested in learning about, as far as omalizumab.
As far as we're concerned, Yaron, this is going to be, you know, paradigm-changing, these data if they hold up the way we hope that they will, right? You know, it's going to be certainly something that the people that are writing the guidelines for CSU want to see, the complete response, but then the next step is how long can you keep them in remission, which will be critically important.
It also begs the question, is the goal to get someone to the deepest CR and keep them there, you know, in the 70%, 65%, you know, 70%, or, you know, being off therapy for 24 weeks, and I'm totally making it up, having a decrement of X, whatever that is. Now, if it's 2% decrement, it's not a big deal, but if it's bigger, what's the right way to think about strategically? How do you develop a drug?
I think there are meta-analyses out there about how some patients spontaneously respond to their urticaria, and we think that that's in the low teens overall. The reason why it's a bit complicated is that these meta-analyses have all sorts of patients in there, mild, moderate, and severe. I think part of what we're going to try to do with our study is to see that, are the severe patients any different than the moderate patients in our study? That's something that we're also looking to do. It's around, you know, low teens. Anything well above that will be certainly exciting.
Yeah, and in the phase III, it's a 48 or 52-week treatment duration, and then there is an optional OLE, right? There's no treatment-free period.
No, there is actually, the way the phase III is designed right now, there is a treatment-free period, but we're talking about adding a long-term extension so that we can, you know, ask some more questions.
I see. Right now, they finish therapy, they go on a treatment-free, and then you will start the OLE thereafter. I think you initially talked about the next update being at EAACI in June, in Glasgow. That sounds like a good time frame for it. A good time to do that. What about maybe reversibility of the AEs? Maybe talk about that and what we might see at EAACI.
Yeah, the most common AEs that we see on the study are mild. They're these KIT-mediated AEs, so hair color change, hypopigmentation, and neutropenia. You know, neutropenia AEs actually reverse while on study, but the neutrophil count does go down throughout the study, and we expect that to come back up. You know, the hair color change is a well understood, KIT-mediated effect that we expect to reverse. We have seen some reversals, and we can, you know, see more of that. Same thing with the hypopigmentation.
The hypopigmentation was even sort of late onset to begin with, right, in patients. And it's very subtle. I mean, you've shown the pictures. I think a lot of investors were concerned that it's profound. It's very scattered and subtle. It happened sort of late to begin with. It's going to be important to see reversibility. Do you feel like you also need to treat for longer to really understand kind of, is there a max hypopigmentation that has their ceiling effect?
I mean, it doesn't seem to get worse once it shows up so far. I also did want to mention that to your point about it being mild, nobody has discontinued treatment for hypopigmentation. You know, because it did have later onset, you know, we do want to look to the follow-up data for, you know, for reversibility.
Yeah. For the phase III, is there any sense, and I know you have in guidance, how long would it take to enroll?
We guided from the very beginning that it would, we were guiding to two years of enrollment, and obviously we're trying to get done faster than that. The only guidance that we'll give you is that, you know, we're happy with what we're seeing and we're on track.
Is it two years for both studies together or for each study two years when you start?
Both studies two years when they start.
Okay, so let's, I'm going to maybe talk a little bit about those, the EMBARQ- CSU1 and EMBARQ-CSU2. You're obviously testing a dosing using a loading dose. Is there even a thought about evaluating less frequent dosing too as maintenance?
Certainly not as part of the phase III study. You know, we included the loading dose to really more rapidly bring tryptase down and mast cell suppression, as well as to make up for the fact that with a flat dose and a very large range of weights in patients, you really are getting a lot of variability in exposure. You know, we feel very comfortable with the loading doses in terms of expected outcomes. I think in real life, there will be a lot of opportunity to consider, you know, for different patients how well they're doing, how frequently they give the dose. It is remarkable that we have a biomarker like tryptase that can really help in that as well.
Is that something you do as a phase IV? Is this something you do as a phase III- B?
You can do it in many different ways. It can, you know, some people, you could put it as part of the long-term extension. You could have separate studies. As Tibor was alluding to, once you get the drug approved, people themselves start to play with that, like Xolair. Many people are not on the labeled dose of Xolair. They're on some, you know, either dose escalated or, you know, different intervals that, you know, people play with it.
Yeah. Within the phase III, the primary endpoint is going to be in all patients, but that's going to include, you know, patients who are naive to certain patients who failed Xolair. Are you stratifying and would you have secondary endpoints looking at each subpopulation?
Yeah, we're stratifying. One of the stratification factors is omalizumab, experienced or not. We have sized the studies so that we can look at the omalizumab refractory population and say something statistical about the primary and key secondary endpoints.
Okay. When there's a lot of competition coming, right? That's something we get a lot of questions about. Dupi is about to get approved and Remi is going to get approved potentially by the end of the year. You are on further the calendar, you're sort of the next one up. This is a market that right now is about a $2 billion market based on Xolair, right? Severely underpenetrated and very much fragmented, mostly non-dermatology. Dupi inevitably probably is going to get some usage in dermatology because they're so used to it. Remi will have to exactly see who's going to use it. You have the best efficacy. Typically, historically, derms have really not treated CSU much other than oral antihistamines. As you think about kind of positioning, how do you think the market's going to shake out?
You know, people have asked us that a lot. I think, you know, the way we would enter the market is behind Xolair. Certainly, I do not think that that is any big stretch. I mean, Xolair has been around a long time. It is a good drug. It is going off patent. So theoretically, it will be relatively cheap. It is interesting, some of the comments we heard that Novartis is going to try to position Remi as a pre-biologic. If they do that, then, you know, we just kind of wonder if Xolair post Remi is going to be that effective. We think the allergist will take up Barzol pretty well. We are also hoping that during the time of development, we are in atopic dermatitis. We are in prurigo nodularis.
The derms are also going to be in our CSU and CIndU studies that by the time that we, you know, we hope to get approval in the CSU, that we will have enough derms that have had experience with Barzol in these indications. You know, we're hopeful that if that works, then the uptake with the derms will be more than, you know, we see with Xolair now, which isn't much. That's how we're thinking of it.
Okay. If anybody has any questions, feel free to just raise your hands. I'll turn it over to Jane.
Thanks, Yaron. Just a few quick questions on CIndU. I know that you've shown really good CIndU data as well with high rates of statistic complete response rates across both Cold U and symptomatic dermographism. I think the next update is going to be 44-week data, again with 20 weeks of treatment followed by 24 weeks of follow-up. Is it reasonable to assume we'll see that at the same time we see the 76-week CSU data?
No. No, we're going to have it.
One data set at a time.
Yeah, it's one stage set at a time, but it will be not too far after that.
Got it. Sometime in age two.
Yeah.
Great. I know that your phase III CIndU program is on track to start in 2025. I was wondering if you can give us any more granularity on kind of precise timing, kind of how you're thinking about the phase III design and dosing. Specifically, are you going to go with these kind of two parallel trials like you did with CSU? Are you going to take one or two doses in? I know that you've seen a little bit of difference in kind of, yeah.
Once we get alignment with the FDA about what we have to do with, especially one or two studies, you know, we'll give you a further update then. We are still on track to have it started by the end of the year.
Great. Do you have any idea about one or two doses though per study?
Probably go with the two doses.
Yeah, and it does depend on one or two studies, you know, if we're going to put the whole program together.
Right. I do want to talk about the additional indications for barzolvolimab. I know that's pretty exciting that you have EoE data coming up in the second half of this year. Of course, fully enrolled. I was wondering for EoE, kind of what is the role of mast cells here? Because usually thought to be kind of eosinophil related.
We're going to find that out with this drug that clearly we expect to be just as effective at depleting mast cells in the esophagus as it is in skin. There's a lot of evidence for the role of mast cells based on histologic data. Clearly a lot of mast cells involved in the inflammation. We know that mast cells are a big contributor of some of the cytokines like IL-13 that drives inflammation. We also know that mast cells play a crucial role together with the sensory neurons in mitigating and driving pain associated with these patients during swallowing. While it's predominantly circumstantial evidence to this point about the role of mast cells, we know that the other major culprit, eosinophils, has kind of been ruled out as a driver in the disease.
We're, you know, very eagerly waiting to see the data of what happens when you take mast cells out.
Right. Do you think that barzolvolimab will have any impact on kind of eosinophil levels as well as mast cells?
We would expect that because mast cells do recruit eosinophils and they do help contribute to their activation. You know, we will be capturing that data along with all of the other histology data.
Right. Do you have any kind of clinical or preclinical data that could give us a sense of what degree of reduction we might expect?
I don't know if this is how relevant this is to the human EoE situation, but we did run a feline asthma model in which we used a predecessor molecule to barzolvolimab. That did lead to about a 50% reduction in EoE in that disease model setting. Again, you know, it's a different setting, but perhaps some of the similar interactions are going on.
Right. From a regulatory perspective, do you think that it's going to be enough for barzolvolimab to show kind of dramatic symptom reduction? Or do you think the FDA is going to want to see some eosinophil reduction as well?
The FDA has a guidance document for EoE, which was written in, I think, 2018 before a lot of data came out. In that document, they specified that they wanted to see histologic improvement in terms of eosinophils as well as symptom relief with, you know, the dysphagia symptom questionnaire. Interestingly, only one drug has succeeded in meeting those criteria, which is Dupixent. Many other drugs have succeeded on the histologic endpoint, but not on the symptom relief. The way our study is designed is we're looking at reduction in mast cells as our primary in this phase II study. We are looking at all the other endpoints to see, you know, to see what happens.
After we get the data, you know, we'd obviously have to have a discussion with FDA about what seemed to be the most appropriate endpoint for this kind of agent.
Right, right. In terms of dosing, I know I think that for the EoE study, you're going with 300 mg every four weeks. I was wondering why, is there a reason that you expect there might be a need for higher dosing or more frequent dosing in EoE versus CSU?
We think that there may be differences in dosing in different indications. The direct example that we have is prurigo nodularis, where in the phase I-B, the 3 mg per kg dose worked better than the 1.5 mg per kg dose in terms of suppression of tryptase, which was not true in urticaria in phase I-B with intravenous dosing. The other example would be Dupixent, where for most of their indications, they have every two weeks, but for EoE, they had to go to every one week to get efficacy. You know, there may be differences between indications. We just wanted to use a higher dose here just to give ourselves the best chance of seeing efficacy in this initial study.
We did not want to underdose in this study, right? These studies aren't cheap, so we wanted to make sure.
That makes perfect sense. I was just wondering if you'd give us any more details. Remind us what kind of the inclusion criteria would be around background medications in the EoE study in terms of like obviously like steroids, PPI, antihistamines, and then maybe whether they could have had prior Dupixent.
Yeah, so they definitely, they can have had prior Dupixent or anything else. They can be on a stable regimen of other drugs, just it has to be a stable regimen over time. Steroids are discouraged in the study.
Discouraged or excluded?
Discouraged unless, you know, rescue type situation.
Oh, I see. You mentioned that Dupixent is the one approved drug in EoE. Given that there is already kind of one player here, where do you see kind of the largest unmet need? Also, do you have a sense of what Dupixent uptake has been so far and maybe what the response rate has been? Like what percentage of patients don't have an adequate response to Dupixent? Early stages, but if you have any tolerance.
As far as the uptake, it's too early to tell, to be quite honest with you. You know, and again, we have no idea what the reimbursement rate here is. I mean, they're dosing every week. We don't know what the pricing is and what the reimbursement levels are. It's still too early to tell what the uptake would be. As far as the only thing we can tell you is that the PIs and the patients were enthusiastic about getting on the study, even though there were a lot of biopsies that were taken here. It was a pretty hard study to do as far as what the doctors were looking to do as far as biopsies and what the patient had to go through. Even with that, we accrued it in fairly good measure.
You know, there's a lot of need as far as we're concerned.
What specifically are patients kind of still lacking even with Dupixent? What are you trying to improve on in terms of efficacy with Dupixent?
At the end of the day, getting rid of the pain and being able to swallow. I mean, a lot of these people are on a restricted diet. They can't, a lot of them can't eat solid foods. I mean, you want to get them back to a normal life as much as you can. And, you know, we're looking to see if the drug can do that.
Right. So here you're looking for kind of getting depth of response versus maybe hitting a broader population of people versus Dupixent.
Yeah, we're looking for depth of response. I mean, if we can get a patient back to somewhat normal life, I mean, I can't imagine, I mean, look at me. I didn't have many liquid dinners in my life. You know, you can imagine that patients want to get back just to a normal life.
Right. Also, to touch on PN, enrollment's also ongoing for your PN study. Do you have any guidance that you can provide updated for when we might see data from the study?
2026.
2026, all right. Is there anything you want to highlight about kind of the differences we might see in trial design in the phase II versus the phase I?
Oh.
Loading dose is the biggest thing, right?
Yeah, loading dose, subcutaneous dosing. I mean, much larger study, placebo controlled, you know, it's a classic phase II study, you know, looking at two dose levels versus placebo. We look at similar endpoints, you know, which is, you know, the percent of people with a four-point reduction in the Worst-Itch NRS and the Investigator Global Assessment. I mean, it's a, the phase I-B was a small study. This is a real phase.
We also think a lot of the differentiation is going to be in the, you know, how we deal with the lesions, because that's where the mast cells reside. So if we can, you know, get rid of the itch and clear the lesions, then those are two big differentiators that are hard to overcome.
Right. What's the time point for your primary? I can't remember.
12 weeks.
12 weeks,
got it. Similar to your other studies. Finally, you have an atopic dermatitis study that began December of last year. I was kind of wondering if you could go over why you chose AD as kind of your next indication for barzolvolimab, how are mast cells implicated here versus in all of your other indications?
You know, mast cells are implicated in a number of different parts of AD pathophysiology. I mean, the most obvious one is probably itch and from what we saw from prurigo nodularis, that's what kind of got us thinking about atopic dermatitis. You could also see roles in terms of, you know, recruiting other cells and in terms of the barrier function. You know, mast cells, there's evidence for mast cells playing roles in all of those. I think that's what got us started in AD. Do you have anything, anything else to add to that?
No, no. Again, there's correlations with higher levels of stem cell factor correlating with disease. Yeah, we think that itch is one of the most important aspects of the pathophysiology of the suffering of these patients. Certainly that can be very similar as what we see in prurigo.
Right. There's a lot of read-through there from PN to AD a little bit, on symptomology at least. How are you thinking about patient selection for the trial? Are you thinking a priori that there might be any kind of subsets of AD patients that would be particularly amenable to a KIT-targeted approach?
No, we're looking, you know, we're looking at a pretty similar population to what Dupixent looked at. You know, we've tried to keep similar inclusion criteria. You know, we know that some recent studies have, you know, the thought is that more patients have had mild disease and that's led to failure. We're trying to definitely keep to a, you know, moderate to severe population. You know, I don't think we have enough evidence or idea yet about how to divide it into subsets. We're just going from.
The way we're envisioning the study is you have your Dupixent patients that fail and any of the IL-13s that fail or even some of the JAKs. It is an all-comers study for us. Hopefully, that is a way to kind of minimize the placebo effect, that you've had these patients that have already failed prior biologics. The way we're envisioning the market for ourselves is post-Dupixent, pre-JAKs. That is where we think that barzol would play well. It is an all-comers study and I would not be surprised if the vast majority of the study is post-dupi failures.
Okay. And then to round out, I want to talk about your pipeline. Obviously, you have another asset, SCF and TSLP bispecifics, CDX-622. You actually recently started your phase I study or SAD-MAD study in December of last year. Yeah, so what can we, like, when can we expect data, obviously, from this trial? I know it's early days. And then when we do, what are we focusing on here? What kind of markers are you going to be using to inform your dose selection? Obviously, for mast cells, it's really easy as tryptase. On the TSLP side, are you going to be looking at eosinophil reduction? Or I know it's kind of difficult in healthy volunteers.
Yeah, we are looking at tryptase. I think from the healthy volunteers' point of view, obviously, it's safety. We have a new molecule. It's aimed to eliminate or deplete mast cells at the same time as shutting down this alarm in TSLP. We, you know, don't expect to have any additive safety concerns. We think this approach is going to be very good from that point of view. We'll be looking at PK for PD. We're going to focus on tryptase. We do expect to be able to show target engagement for TSLP in the healthy volunteers. We will have to follow this up very quickly with a study in patients. We're proposing asthma patients that will really help give the proof of concept around both the TSLP side as well as the mast cell stem cell factor side.
Right. If you're looking kind of towards asthma, what kind of additional benefit do you think you'll get with this kind of mast cell inhibition or mast cell depletion versus what you can already get with TSLP inhibition with existing kind of obviously Amgen and Tezspire, and also there's a bunch of other TSLPs in development.
TSLP is shown to be effective both in the eosinophil high and low population, though clearly much better with eosinophil high. While it can have a modest effect on mast cells, TSLP really doesn't impact the mast cells very dramatically. We do think mast cells are contributing significantly to asthma. We believe the evidence for that would be, you know, most clearly demonstrated in the eosinophil low asthma patients, which still there's a lot of room to improve. We also think we could deepen efficacy in the whole asthma population, which, you know, still have certainly room to get better.
Right. I know it's very early days, but are you thinking anything about how you're going to dose this? I know the trend for TSLP agents is to try to get this very extended dosing regimen. Have you thought about it at all for CDX-622?
We'll have to get the data. We need to get the pharmacokinetic and pharmacodynamic data. Our general view on this is you want to make it as convenient as you can for patients. What is most important to patients is their clinical benefit.
Right. Lastly, I think that you mentioned that you were in development or you're developing a subcutaneous formulation. Obviously, I think it's IV right now. Can you give us an update on where you are in that process?
We're in the manufacturing process. We want to introduce that before we get into any larger patient studies. And we're well on our way to do that.
Right.
I'm going to have it this year.
Oh, okay, this year. Is this mainly directed toward asthma or are you looking at other indications for this bispecific?
Yeah, no, that's really our initial proof of concept. We think there's a lot of opportunity for these two pathways in a number of different pulmonary indications, fibrotic indications. We are looking at this pretty broadly, obviously waiting to get the proof of concept before we step into those broader indications.
Great. We're coming up on time, Yaron or the audience, if you have any last questions.
Coming back to Yaron's questions, how the phase III, you said you guided for two years where you initially said, so remind me when did.
July of last year.
July of last year. After the last patient is enrolled, how long between that and the last patient visit?
24 weeks?
Correct.
24 weeks. Yeah, we say the traditional four to 10 weeks to clean up. Yeah.
Maybe a final question just on PN. What's the standard of care now? Is it essentially dupi increasing?
Dupi and Galderma are there. I don't really think one is placed over the other. I think Galderma's data was just as good, if not better.
Yeah, I think dupi is used, but Galderma is gaining ground. It's what we are.
They both just got approved so early that it's hard to tell who's in front.
Are there any biologics used off-label for PN or EoE historically that I can think of?
Not that I can tell off the top of my head.
Terrific team. I think we're at time. Thanks so much for joining. We appreciate it.
Thank you.
We'll continue to follow. We'll see you when blocks go.
Appreciate it.