Good morning, everybody. Welcome to the first day of Cantor's Global Healthcare Conference. Really excited to be joined on stage with the Celldex management team. We have Dr. Tibor Keler, the CSO, Anthony Marucci, the CEO, and Dr. Diane Young, the CMO. And I'm joined on stage with Eric Schmidt, who co-covers the company with me. Thank you so much for being here today. Really appreciate it.
Thank you for inviting us, Kristen. We really appreciate being here.
Absolutely. So to start things off, would love to just hear a general update of how things are going, and yesterday, you put out a press release announcing that you'll have data in a few short days here. So what can you tell us about what to expect there?
Sure. So, we put out a press release yesterday, as you said. It'll be on our Phase II CSU study, our update to the 12 weeks, where we will present 52-week efficacy and safety data on the primary and secondary endpoints. That presentation will be at EADV in Amsterdam. And, you know, we're excited to present the data. This is a very long dataset. It's a number of 208 patients, so it makes it a large data, safety and efficacy dataset as well. So we're really looking forward to presenting that data, and as you know, based on our 12-week data, we initiated the Phase III studies in CSU earlier this summer. So all things are going well.
And then in October, we'll present the CIndU data, the twelve-week full dataset of primary and secondary endpoints. So we're quite busy.
Okay, great. Maybe just to take a step back here and understand your approach in more detail. There's been a lot of noise around c-KIT, thanks to the work that you've done over the last four years, truly pioneering why this mechanism is so relevant in mast cell-driven disorders. We saw some data from Dupixent last week that looked pretty disappointing. So why is it that this mechanism is truly so much better than anything else we've seen?
I'm happy to answer that, Kristen. We believe that mast cells are really at the root of urticaria-driven symptoms, and there are many different ways that mast cells can get activated, can drive disease. We think the best way and best approach here is to actually eliminate the mast cell altogether, not target a specific pathway that leads to their activation, and that's what KIT inhibition does. KIT signaling through stem cell factor is required for mast cell function and survival, and barzolvolimab is just a very highly potent, very effective KIT inhibitor, which drives these cells into apoptosis.
So, let's talk about CSU in a little bit more detail here first. So you did start the Phase III studies. If we see data that's relatively in line with what we saw in Phase II, which market segments do you believe that physicians are likely to treat patients for?
Like we've said, based on our Phase 1a and now our Phase 2 data, we can treat the whole population, whether you're biologically naive, whether you're OMA experienced, or whether you're OMA refractory. The Phase 3 study we've made large enough so we can, you know, get statistics around the OMA refractory population. So we believe if the Phase 3 is successful, all patient populations will be able to be treated in CSU with this drug, which as compared to Xolair, it's only the biologically naive patients that they've been approved on, and that's quite frankly, the only population they have data on. We know Dupixent failed in the Xolair failures, and that's the only other drug that's been tried. So we, you know, we have the whole market if we get approved.
How are you thinking about the breakdown between dermatologists and allergists? How are they prescribing it now, and then how might that change?
Yeah
... down the line with better drug options?
So with our analysis, what we've seen is that the Xolair prescribers are vastly, you know, allergists, approximately 80%. And in fact, behind the allergists, you got the primary care physicians, then you got nurse practitioners that prescribe Xolair more than the derms do. When you look at Dupixent, it's probably a, a pretty even split between allergists and derms, but you can see that's where they're targeting, is the dermatology population. Where we believe we would be able to target is, is obviously the derm... the allergists, because they've done the CSU and the CIndU studies.
But because we've also had derms in the CSU, CIndU, PN, which is primarily a dermatology-driven disease, and now going into AD, which is completely a dermatology-focused disease, that by the time we get approval for CSU, we'll have enough dermatologists, both here and in Europe, that will have enough experience with Barzol, that they'll be comfortable in prescribing it.
How do you size up that total market for CIndU and CSU in terms of patient numbers?
Yeah.
Who's failed Xolair already, and-
Yeah. We believe the market overall, Eric, between the US and Europe, is about 750,000 biologically naive patients. And we think that there's at least a 50% failure rate on Xolair, that patients either don't do well or don't respond to it or aren't well controlled. But again, because our data shows that we work, no matter what, you know, patient population you're in, we think that gives us a lot of the ability to grow. And we think that the CIndU market, and the CIndU is comprised of nine different indications, the largest of which are cold urticaria, symptomatic dermographism, and cholinergic urticaria. But we think that that's about 25% of the CSU market globally.
Maybe just to talk about safety for a second here. Do we, do we have a sense of any long-term consequences of depleting mast cells?
Yeah. So, you know, mast cells are an essential cell in the immune system. They're a very old cell, like, you know, I mean, evolutionarily. You know, I think there's really not a lot of data on what happens if you deplete mast cells. There's some data from chronic myelogenous leukemia patients who took imatinib for a really long time, and a small subset of those patients were studied specifically for consequences, and they showed that their mast cells were depleted, basically, and they didn't really have any consequences that they could attach to it. I mean, I think the thing you'd most worry about would probably be infections since it's part of the immune system, and that's certainly something, you know, we look for very closely in our studies.
Are there genetic conditions of mast cell dysfunction that can help inform?
Not that I know of in people, but certainly in mice, and these have been looked at. The issue there is they're typically either KIT or stem cell factor-associated mutations, and they impact not only mast cells, but other parts of the hematopoietic system.
So when we see these longer-term 52-week data next week now, it's one of your largest long-term safety follow-up studies. What would you think, Diane, should be our learnings or take-home messages from that database? What would you like us to see?
Yeah. So I think the main thing is for safety, of course, you know, you wanna see a longer duration of safety. We wanna see, you know, what's the frequency of adverse events? You know, how do things evolve over time? You know, do you have, you know, more infections? You know, things like that. I mean, this is a really important data set. I know a lot of people are wondering, does the hematology get worse, you know, with. You know, so this is gonna answer all of those questions. From an efficacy standpoint, you know, we had very outstanding efficacy at twelve weeks, but we certainly wonder if, you know, with longer administration, do you have, you know, a deepening of response?
So, you know, there's, there's a lot to look at in these data. Mm-hmm.
Will we get to see the fifty-two-week data from patients previously on Xolair?
Yes.
Mm-hmm.
Awesome.
Just remind us of Xolair's experience long term, say, over a fifty-two-week period.
So that's the interest in Xolair. Did their controlled studies only for 12 weeks or for six months. So, you know, there are some articles out there about, you know, long-term effects, but they're not based on measuring it the same way, so, you know, it's a little hard to tell. You know, certainly at 12 weeks, their complete response rate is 36%, you know, which is lower than what we saw.
So on safety, you know, the Street does seem to be focused on the anaphylaxis case. This is now one out of 500. Grade 3 neutropenia has come in at about 1%. Why shouldn't people be overlooking these facts?
I think for anaphylaxis and hypersensitivity, these are things that are described in the label of every biologic that's out there. You know, it's an expected thing with biologics. You know, I think, you know, in this case, we just have to, you know, see eventually what the full data set shows. Neutropenia, we've repeatedly said this is an asymptomatic laboratory value, you know, and it's very predictable. You know, we see a pattern where patients decline in the first four weeks and then stabilize, and then, you know, we'll kind of dip in and out occasionally of lower levels, and then when the drug's gone, it comes back up. Most importantly, it's not associated with any clinical consequences. You know, we're not seeing an association with infections. You know, people are able to stay on the study.
So I think, you know, the fact that it's so predictable and it's not having consequences is really the important take-home.
Yeah
with that neutropenia.
That definitely is the important take-home message after all of this, is that it's predictable and that, you know, the manifestation of infections is not there, and so there's no association with infection. It's just a normal laboratory dip.
It's now been over four years since we can truly say you've been the pioneer here, excuse me, with your healthy volunteer data that were so translatable to the now clinical data we've seen. So obviously, c-KIT has become a target of interest because of your work. So I wanted to ask what advantages your approach has, specifically as an antibody, but then also through preventing the receptor dimerization versus stem cell factor binding directly.
We really like the approach of using antibodies because of their specificity-
Mm-hmm
... relative to a small molecule inhibitor approach, and antibodies also offer the opportunity to engineer your product to have a specific profile, for example, engineering in long half-life, which is really important for these types of indications. With regards to our specific mechanism, which is an allosteric inhibition of kit signaling through stem cell factor by preventing the dimerization of the receptor.
... This, in essence, yields the same result as preventing SCF binding to the KIT receptor as other KIT monoclonal antibodies do. But we do feel that, besides this being a very highly potent mechanism, there may be nuances to this approach, particularly in the context where you have, for example, in the bone marrow, where stromal cells are expressing high levels of stem cell factor on their membrane associated with hematopoietic cells expressing KIT, that some level of KIT signaling could possibly get through. We don't know that for a fact. This is theoretical, but based on the published data, there may be some differences in the impact on hematopoiesis or erythropoiesis between antibodies that bind block stem cell factor binding versus this allosteric mechanism.
So, thinking about the Phase III study that's ongoing, obviously I'll be patient and wait for the data next week, but what are the key differences in the Phase III trial relative to what you did in Phase II? And you're gonna have a bolus of patients, eighteen hundred, in addition to your earlier work. You know, why is this a good number, and will this lead to physician comfortability?
So the key difference between the Phase III and the Phase II from a design standpoint is that for the Phase III, we've added a loading dose to our dosing regimen, and that was based on PK/PD modeling from the Phase II study. You know, suggesting we might get, you know, even a more rapid onset of effect in the beginning if we added a loading dose. I think the other thing is, of course, it's a you know, it's a larger study, much larger study with many more centers, which is a big thing. And the other thing is that the study is, as you say, larger, and in this case, it was actually sized to be able to allow us to say something statistically about the omalizumab refractory population, which is a difference.
In terms of other aspects of the design, we've really tried to keep the Phase III very similar to the Phase II in terms of inclusion, exclusion criteria, in terms of endpoints and all those things. So that part of it we're trying to keep, you know, as similar as possible.
With the loading dose, and I assume you're modeling that on serum tryptase levels and hoping to hit those harder and faster, are you trying to get to a faster onset of action, obviously? Did you see in the first few weeks, you know, not the efficacy that you think you could have achieved with the loading dose? Or what was the rationale clinically for the loading dose?
One thing is, I think fast onset is a really important thing in the disease, and you know, with subcutaneous dosing, you do tend to get a more gradual response. But the other thing to take into account is that we think there may be a weight effect, and we're giving flat doses. You know, we think that you know, with a loading dose, you know, we could have better effects in the overall patient population, those that are lighter and particularly those that are heavier.
So the-
So-
Sorry, go ahead.
So in the Phase II study, the range was up to one hundred and sixty kilos, and using a flat dose. So, you know, we think that adding the loading dose could especially help those heavier patients get under control faster. And certainly, the Phase II data set's instructive for us. You know, we loved the efficacy data that we've seen, but, you know, we're also seeing if we can improve on that, earlier and, you know, more deeply going forward.
The fact that you've gone to a loading dose in the Phase III also suggests that, you know, after this maybe initial window of suboptimal dosing, you're, you're seeing better control, disease control in subsequent weeks. Is that, is that an accurate statement of the Phase II and what we might see in this longer-term follow-up?
Yeah, I think we're saying we're deepening of response, so we're hopeful that's the case. Also, we'll find out next week.
Yeah. So, so urticaria was really the poster child for barzolvolimab, showing that targeting mast cells can have great success. So since then, you've built a pipeline around this drug, and it truly is a pipeline and a product potential. So, I don't know how much you're gonna like this question, but I wanted to see of all of your indications, if you can rank for us or give us a sense of how you're thinking about the, the likelihood of success.
Oh, God.
It's like, which is your favorite-
Which is our favorite child? I think they all have a high level rate of success, but they're all different, right?
Yeah.
So PN and AD are dermatology-driven diseases. Certainly, CSU and CIndU are the ones off the top of your head that, yep, those are really mast cell-driven diseases, so you would hope for success there. So let's say they're the two kids that are off to college, right? They've proven something, but now you really gotta spend a lot of money on them. EoE is interesting because we think that mast cells play a greater role in the area of dysphagia-
Yeah
... and that eosinophils have proven not to be, the big winner there. So I would imagine that that, for us, is the biggest unknown. So PN and AD, I think we know. CSU and CIndU, we absolutely know. EoE is the one that, you know, we're hopeful that our theory proves right. And if that is right, then that opens up a whole bunch of stuff. So I hope that-
... gives you a sense of what we think.
Yeah.
When you think about PN and atopic derm, the two indications where dermatology is obviously prevalent, what do you think you need to see from a safety standpoint to really get into those markets?
I think, you know, I think we need to see a well-tolerated drug, you know, associated with, you know, great efficacy. You know, something that will, you know, give an advantage over the other things that are out there, and I think there is, you know, room for improvement in those diseases.
Yeah, from an efficacy standpoint, I see.
Yeah. I think it's gonna be your true risk-benefit profile, right? So where we think that we would have the efficacy we saw in the PN study is not only the reduction of the itch but the healing of those lesions, which, you know, I think are incredibly important, and that's where the mast cells reside. So, I think if you can get that dual efficacy in the PN study, you know, we've shown that it's, you know, a safe drug in the Phase 1b, and I think the same thing in the AD. If you can do something with the itch as well as the lesions, and have a, you know, favorable safety profile as we've had, I think we'll be good there, too.
So AD is interesting from the perspective of there are studies that show these patients have increased mast cell numbers. There is some sort of understanding about how mast cells interact with sensory nerves in the skin, and then to your point, we've seen proof of concept in a couple of disease models now around itch. So can you just help us understand the biology a little bit different here? And do we think that in atopic derm, this is gonna be treatment that has potential in everybody? Is there maybe a specific group where we might see the greatest effect based on this mechanism?
I think what's great about barzolumab and our opportunity is to really understand the role of mast cells in these different disease settings. There are still some unknowns. We think our data in prurigo really help establish the role, the connection between mast cells and sensory neurons that drive the itch process, which many of these patients really suffer from. It is, I think, one of the major symptoms for these patients. We do think that they. There's a broad opportunity to impact atopic dermatitis patients. But it wouldn't surprise us as well that in some cases, you know, there may be a more prominent role for the mast cell than in other cases.
And until we do these studies, we really won't understand what ideology, what are the reasons, or the, you know, what kind of patients are responding best.
Yeah. So we're doing work now analyzing patients in the Phase 2 studies, which will not be presented next week, of patients that had comorbidities. And I think we'll see some atopic dermatitis comorbidities there. So we'll get some learnings from those patient populations. But certainly, we think that there are, you know, patients in the AD space that probably do have more of a mast cell component.
Mm.
and probably won't do as well on Dupixent. But, you know, again, our strategy in AD is not to go head-to-head against Dupixent, right? Well, I mean, we're gonna do an all-comer study, but we believe that, for us, the space is gonna be post those Dupixent either failures or they're not responding well and before they get to the JAKs. I think that's where our sweet spot's gonna be.
Is there a diagnostic or biomarker strategy you could use upfront to identify a more mast cell-driven patient in terms of these dermatologic conditions?
Yeah, I think we're gonna talk to KOLs and see what the right tests are. But, have you had-
Well, I think we're approaching this kind of agnostically, and we'll see if we learn something through our studies-
Yeah
... that might point to a particular biomarker that's relevant.
Okay, so moving back to PN, I think, you know, something that's often forgotten is this was a single-dose study, and you saw the benefits that you did.
Mm-hmm.
So where can we go from here now if we think about chronic dosing, and do we have a sense of what the competitive profile could look like there?
Yeah, so I think, it was really remarkable in that study that with a single IV dose, and particularly at the higher dose, the three milligrams per kilogram IV dose, we did see, you know, very early and dramatic reduction in itch, and we were seeing early lesion healing, which is very intriguing. So certainly, you know, we're hoping that with chronic dosing... And again, we've added loading dose to that, those regimens as well. But, you know, we're really hoping to see, you know, even better, efficacy and, you know, kind of find out what the drug can do.
Thinking about this market size, how are you thinking about the potential? You know, obviously, safety's important for clinicians, but is there a measure that is most critical to them?
I think, again, reducing the itch for those PN patients is hugely important, and quite frankly, it's probably not spoken of enough, but getting rid of those lesions, I mean, that's an effect that people don't even... You know, they stay out of society because of-
Mm
... some of the, of the look. So we think that that's just as important, but certainly, the itch is the first component that we need to tackle. And then, because those lesions have those mast cells, we think we will have a big impact on the lesions. So you get a dual effect, and it's an older population. But we think the market opportunity there is about 75,000 in the US, biologically eligible, which again, makes for a very good market.
...And then maybe I will spend a little bit of time on EoE, recognize it's the higher-risk child. But in terms of this Phase II data, like, what's gonna be the go, no-go decision? Just, is 12 weeks gonna be long enough to understand the potential in this? And can you give us a sense of the esophageal intraepithelial mast cell counts? How does that correlate here?
Yeah. So it's really interesting because we're really undertaking new exploration here because our in this study, and it, you know, it's an initial study, but our primary endpoint is mast cells, and there hasn't really been good quantitation of mast cells because everybody's focused on eosinophils-
Yeah
In this study. So we have eosinophil counts as a secondary endpoint, and we certainly, we think that, you know, by reducing mast cells, and we hope to reduce mast cells the same way we, you know, to the same degree that we saw, you know, a reduction in skin mast cells. So that's the first thing. But then we do think if we reduce mast cells, we will reduce eosinophils as well. We just don't know how well. So we're looking at those things from a histologic standpoint, and then we're really paying attention to dysphagia because that's where everybody has failed. I mean, there's, you know, numerous drugs now that do deplete eosinophils, but, you know, the patients are still symptomatic. And so, you know, we really, you know, we...
We do think that at twelve weeks and with the number of patients we have, we should be able to see something, you know, that will give us, you know, confidence about dysphagia. That would be very important before undertaking, you know, more advanced studies.
Okay. And I don't think a lot of people are familiar with the fact that you also have a bispecific in development. What's the latest with that program?
Go ahead, Tibor.
Yeah, so, as we know, these inflammatory and autoimmune diseases are complicated. They typically involve multiple pathways. Obviously, urticaria is really mast cell driven, but we recognize that in many other settings, mast cells are contributing to the, pathology and not necessarily the sole driver. So the concept behind our bispecific program is really to build off what we're seeing with barzolvolimab, where we are able to impact or deplete mast cells, but also target another clinically validated important pathway. And our first bispecific is CDX-622, which targets, TSLP, this, Th2 alarmin that certainly is validated in asthma, but also, has good clinical data in a number of other settings, together with stem cell factor, in this case, with our bispecifics. We're neutralizing stem cell factor instead of, directly, binding and inhibiting KIT.
We think that's a better approach for the bispecific. And we're very excited to bring this into the clinic this year, initially starting with healthy volunteer studies. So, look forward to presenting data on that next year.
So you.
Thank you for that. And maybe just to close, why should investors in this room consider looking at Celldex at this time?
I think we're at an inflection point, where we have proven, in my mind's eye, we have certainly a proof of mechanism. We have a proof of concept. We have one of the largest, efficacy and safety databases in CSU and CIndU. And in these types of indications, I think your Phase II data is certainly a good barometer of what Phase III will look like.
You know, I think we've been very, very conservative in our conversations with you and others over the years, where, you know, as we got into Phase II, we said, "We think we have a drug." And then as we got some data, it's like, "We're very happy with this drug." And I think now that we're in Phase III, I can, you know, very look everybody in the eye and say, "We have a drug." And, you know, the Phase III, we're looking forward to completing the Phase IIIs and putting this drug on the market. This is the drug, and we think it's a damn good one.
Thank you. Always a pleasure hosting you. Appreciate your time.
Thank you.
And we'll all be paying close attention.