Okay. Good morning, everybody. Thank you so much for being here. It's day two of Cantor's Global Healthcare Conference. I'm Kristen Kluska, one of the analysts at Cantor. Very happy to have the Celldex Therapeutics team here with me today. We have Anthony Marucci, the President and CEO, Dr. Tibor Keler, the CSO, and Teri Lawver, the CCO. Thank you all so much for being here.
Thank you for inviting us. Appreciate it.
There's clearly nothing going on at Celldex for this year, so I'm sure we'll think of something interesting to talk about instead.
Okay, great.
Maybe just to kick things off, do you mind providing us with a high-level overview of the company?
Sure. We are an antibody company by birth and by trade. We have been in that area of the business for our whole lives. Our lead program, barzolvolimab, is an antibody that targets c-KIT, and it is currently in phase III development in three indications, CSU, symptomatic dermographism, and cold urticaria. We had completed our phase III study in CSU back in February, and we are looking forward to presenting the data later on this year, as we have two phase III studies going on in CSU, and one of the largest studies, if not the largest study ever conducted in CSU, with nearly 2,000 patients. We look forward to doing that. Behind barzolvolimab, we have several other antibody and bispecific programs. CDX-622 is currently in early stage development.
It is a stem cell factor by TSLP construct and early days with that program, but everything seems to be reading out very, very well.
We are very excited for these upcoming phase III data, which you have said could come in September or October. Maybe to kick it off on that trial, the phase II one was very successful. How similar are the designs between that trial and the current ongoing phase III ones to replicate that success? What might be the added benefits of the loading dose that's newly being included?
Why don't we talk about the loading dose?
Yeah. Design-wise, the eligibility criteria is exactly the same between phase III and phase II. What we did modify was to include a loading dose before the two regimens that we tested in phase II, which was the 150 mg Q4 week or the 300 mg Q8 week. What we believe the loading dose will do, will not only more rapidly saturate the KIT receptor and reduce the mast cell and symptoms more rapidly, but it also helps us across the variety of sizes of these patients. Of course, we're giving a flat dose here. We think this just gets patients into the zone that they need to be in in terms of mast cell inhibition and gets there faster. We look forward to seeing how that works out for us.
Otherwise, the studies, other than being much larger and many more sites and countries, they are really very similar to the phase II design.
Okay. On that topic, we did get to see the effects of the loading dose with your recent PN data. What did that tell you?
Yeah. The loading dose was used in both dose regimens in PN. One of those is very similar to the doses we're using in phase III. One is actually even a higher dose. We saw exactly as expected in terms of the impact on circulating tryptase on mast cell inhibition. What was very pleasing is, despite this higher exposure, we really saw a very consistent safety, consistent with all of our experience with barzolvolimab, so a very good safety profile.
Okay. Bearing all of this in mind, can you remind us about the trial powering, the secondary endpoint hierarchy, and any other considerations into that design?
Sure. The study was powered for 90% power to detect a 10-point difference in the UAS7 score. What's important to know is we wanted to be able to have that powering for the subset of patients that are omalizumab- refractory. For the overall population, this is powered much higher. It's quite overpowered. But we also wanted to be able to really have statistical analysis on specifically the omalizumab-refractory population. The hierarchy is as you would expect for a CSU trial. It's the UAS7 change from baseline at week 12. Then it's the itch and hive scores separately. We're also looking at the UAS7 equals zero, so no itch, no hives, really the hallmark for barzolvolimab in the studies to date. We will also, in the hierarchy, look at the very well-controlled patients, so UAS7 less than 6. We have an angioedema analysis, the AAS7 equals zero.
Then, of course, the omalizumab-refractory patient population in terms of their UAS7 scores. A lot of important endpoints there that we're really excited to see.
Have you disclosed which of these endpoints and datasets you're going to share with the Street in this initial release versus what you might hold for a podium presentation of some sort?
We will definitely present the primary endpoint. We haven't been specific about the secondary endpoints. I think, clearly, we want to reserve as much as possible. At the same time, we recognize the importance of being able to share information. So we hope to be able to present on some of the secondaries as well.
Okay, thanks. Moving on to the commercial opportunity. Teri, you've taught me a lot about urticaria in these last few months since you've joined the company, so I'm really looking forward to hearing some of your responses and some of the early work you've done since you joined the company 10 months ago. But in general, what do you believe are some of the different characteristics, disease drivers that are truly going to influence the line of therapy that people use barzolvolimab for?
We've identified two natural entry points for barzolvolimab, each with significant patient populations of high unmet need, where barzolvolimab can be uniquely positioned to lead. The first of those is for first-line advanced therapy, where patients are presenting with severe disease and/or severe angioedema. What's the data supporting this? If you look at our phase II trials at week 12, 65% of patients were angioedema-free on barzolvolimab compared to 25% on placebo. That 40% delta is more than twice the delta that's been seen with any other therapy. As a reminder, for dupilumab in their angioedema, they saw no difference versus placebo. There's a significant unmet need in this population. Right now, they're being treated with multiple doses of corticosteroids every year. We all know the toxicity of chronic corticosteroid use.
In terms of the size of that first-line population, in our phase II trial, 36% of patients had both severe angioedema and severe CSU. Even if we assume that the broader population is somewhat less severe than our trial, that still could be 20% of the first-line population where barzolvolimab is uniquely positioned to address their needs. The second entry point is to position barzolvolimab as the preferred second-line advanced therapy. Whether a patient has tried any one of the current approved therapies, omalizumab, dupilumab, or remibrutinib, if they're still experiencing symptoms, itch, and hives on those therapies, barzolvolimab is a unique choice. What's the data supporting this? If you look at our phase II, the results, the high efficacy we saw with barzolvolimab was consistent regardless of prior biologic therapy and regardless of IgE levels. That's a unique characteristic for barzolvolimab.
In terms of the size of this population, when we look at the attrition rates for the current therapies, not inconsistent with what we see in other I&I classes, the second-line advanced therapy population or market could be larger, can eclipse the first-line population in the first number of years of launching, and that's very consistent with what we see in other chronic I&I diseases.
On that first bucket, the patients that present with both severe angioedema and/or severe disease, what is it about barzolvolimab that the drug is specifically working in this population? We've talked about other drugs that may have been effective for other populations of CSU, but not this one in particular.
Well, I think it's directly related to the mechanism of action. Barzolvolimab, by targeting the KIT receptor, which is essential for the survival of mast cells, really depletes the effector cell that's driving the symptoms in these patients. Really, by targeting these cells, by eliminating the cell that's causing the symptoms, including angioedema, we think that's the most effective way to target all of the symptoms, and regardless of the background etiology for the specific patient.
Okay. One of the baseline data sets you shared with us was that of the U.S. patients, more than half of them were enrolled in the U.S. I think there's this misconception out there with investors that dermatologists have been historically more skeptical of using therapies for CSU. Do you believe that's true? If it's not, what is the underlying misconception?
Sure. It's interesting when we look at where in the U.S. CSU patients are being treated, it's almost equally split between dermatologists and allergists. But when we look at where CSU advanced therapies are being prescribed, it's highly concentrated in the allergist community. Why is that? Well, remember, there were no advanced therapies until 2014. Then for omalizumab, we've had 11 years until 2025 with only that one therapy. What's interesting anecdotally, when we are in advisory boards and speaking with HCPs, they talk about being left out of the omalizumab commercial launch. We have several dermatologists who would say to us, "I've never seen an omalizumab rep. That's why I don't prescribe the therapy." I think it's a bit of a misconception that dermatologists are afraid of quote, "the black box." Dermatologists prescribe multiple therapies with black boxes. They're also not afraid to inject in-office.
There are a number of therapies that dermatologists use in-office. As we have seen other therapies come on, dupilumab and remibrutinib specifically, we are seeing more dermatologists come into the space in prescribing these advanced therapies, and we would expect that trend to continue. I think that is a real nice opportunity for market expansion for barzolvolimab.
How much of that is just driven by the physicians are familiar with the drug class for other indications, versus the reps are actually going out to the dermatologists specifically to say, "Hey, we have new treatments for CSU?"
It's definitely both—
Okay.
—of those things. Dupilumab has been a tool in the dermatologist's arsenal for quite some time. They're extremely comfortable prescribing it. It has good payer coverage, so when that CSU indication came along, it was a natural go-to. And of course, remibrutinib, we know that commercially they have a strong presence in the derm offices. We also see the dermatologists very open to prescribing barzolvolimab when we speak to them in market research. These physicians want to help their patients. They want tools in their arsenal to help their patients. And when we're at medical meetings and we see dermatologists saying, "Take back CSU." So the dermatologists have had the CSU patients in their offices and have generally been referring them out when they've needed advanced therapy, and we see that dynamic changing.
Yeah. To your point, they did accrue more than half the patients—
Yeah.
—in the U.S. They were very excited about it. We think that it's certainly an untapped area for advanced therapies.
Thank you. One thing that's been quite differentiated is the profile of barzolvolimab that has shown sustained benefits in many patients weeks after the treatment has ceased. What's your latest thoughts around the hypothesis behind why this might be happening?
Yeah. There are several factors to that. Again, related to the mechanism of action. So barzolvolimab reduces the number of mast cells in people, and this is the effector cell driving the symptoms. Once therapy is stopped, there is a long half-life in this antibody because we have engineered it to have the YTE, and so they do have continued exposure for some period of time. But even beyond when the antibody is around, there is a time during which the mast cells will eventually replenish, and we believe these new mast cells may be less sensitive to some of the triggers that the patients were responding to initially.
This is of course hypothetical, but we do believe that based on the data we have, which is 40% of patients still maintaining a complete response seven months after their last dose, is representing. This is in the context of having mast cells return to normal levels based on their tryptase levels, really suggests that they are not being triggered the same way they were before our trial.
We really believe we're resetting the immune system.
I might note that 40% we see in complete response at the end of six months off therapy for barzolvolimab is the same response rate that we see on competitor therapies while they're on—
Yeah.
—therapy.
How might this profile be able to impact payer discussions, positioning, and frankly, how are you as a company going to make the community aware of these data and findings that you've had?
You asked about payers.
Yes.
From a pricing standpoint, we are committed to a value-based premium pricing strategy for barzolvolimab that we think reflects the clinical differentiation and the value it brings. As we are in preliminary conversations with payers, we see them being supportive of that approach. The most expensive therapy from a payer standpoint is the one that does not work. When you have the kind of consistent efficacy that barzolvolimab delivers and positioning the therapy for patient populations who cannot be addressed with other therapies, that is a very strong value proposition that we can lean into.
As far as getting it to the patients, you do it through medical affairs, you do it through patient advocacy, you do it through generating real-world evidence on top of the large phase III studies that we are doing. There is a number of opportunities to definitely connect it.
Certainly as we are building out the commercial organization, our intention from a field representative standpoint is to be competitive and well-positioned across the offices, across specialties who are treating advanced therapies.
For the longest time, XOLAIR was the only kid on the block. I think we have all done KOL checks, and you found in a real-world setting that they are being creative with using it. They are dosing more often and cutting the dose in half. They are really trying to keep their fingers crossed and see if it works longer. How has the landscape really changed now that if you do not respond to XOLAIR, we know that there are options beyond that, and you may have another one to add for consideration?
Mm-hmm. No physician wants to tell a patient that I have nothing left—
Yeah.
—for you.
Right.
We have seen this in other I&I diseases. When there is only one advanced therapy, you save that weapon as the last resort in your arsenal. It creates a bit of sometimes a rationing behavior if there is only one advanced therapy. We see that changing already in the marketplace with the advent of the first two in over a decade, additional advanced therapies approved in 2025. We have seen, for example, the number of new-to-brand prescriptions across all CSU therapies roughly double from the end of 2024 to the middle of 2026, which we think is a very clear hallmark that patients are being brought into this advanced therapy paradigm quicker, which will drive additional diagnosis. The diagnosis rate right now is very low. It is only 32%.
Between increasing diagnosis and then those patients being brought into and through the funnel faster, it creates a lot of tailwind for growth for the category.
Novartis and Sanofi will do a great job of expanding the market. We just think that, to Teri's point, is a good tailwind for us as we're preparing.
In terms of the upcoming readout, what has your diligence told you will be an acceptable safety profile for utilization? Are these metrics going to change based on the difficulty or the level of severity presented across patients?
I think we're very happy with the safety profile we've seen. We've experienced now so far something like 700 patients through our phase I and phase II studies. It really has been quite consistent through various different dosing regimens and different patient populations. We expect a similar consistent readout in the phase IIIs. We think that's going to be extremely well-received and adequate for the wide range of patients that we might be able to treat.
Okay. We are absolutely rooting for you for this upcoming readout and wishing you all the best into it in the next few weeks. I did want to make sure we could spend a few minutes on the rest of the pipeline.
Okay.
First, for the cold urticaria and symptomatic dermographism studies, how similar is the phase III population going to be to the phase II one? Do baseline metrics play a key role for this disorder, given the primary endpoint in this instance is achieving a complete response versus just a certain number of points?
Yeah. As far as the criteria, inclusion and exclusion is the same as the phase II. We wanted to keep it as consistent as we possibly could. As far as the endpoints that we're looking at, we certainly were very impressed with what we saw in phase II, and we think we can replicate them in phase III as well. Do you want to add anything?
Yeah. Again, we did add a loading dose to the phase III design. From our perspective, we've even optimized that a little bit. Otherwise, complete response to provocation testing has been something that barzolvolimab has done better than any other treatment out there. So we are very pleased with that as the primary endpoint. We think the study should be very successful.
Okay, thank you. What's your latest thoughts around the mast cell involvement in atopic dermatitis based on the readouts learnings from all the trials you've conducted so far, and what's going to be a go/ no-go decision for that program that'll read out later this year?
I can answer the science part. That hasn't changed. Mast cells are upregulated in the atopic dermatitis lesions. They're there, they're activated, and they contribute both to the inflammatory process by release of cytokines, by recruiting immune cells. They also have this interaction with sensory neurons that are thought to be important in driving the itch component of the disease. That science is something that we're obviously testing in this study. We'll have a readout later this year. I think our go/ no-go is really based on the same criteria we always use.
Yeah. We always use. If there's a meaningful impact that barzolvolimab has in the patient population, we'll move it forward. If not, we think that the AD space is well taken care of.
Moving on, the bispecific data for CDX-622 have looked really impressive, and we've been able to see great activity of inhibiting mast cell function with the tryptase measure. What gives you confidence on the targeting of TSLPs, since this is sometimes less obvious to measure?
Yeah. We are confident on the TSLP aspect of the bispecific because the antibody that we've discovered and developed, at least in the laboratory, behaves very similarly to tezepelumab, to every extent that we can test it. Certainly, it's difficult to demonstrate its functionality in healthy volunteer study, which is why we are conducting a phase I study in asthma patients as primarily a biomarker study. We will have readouts that are relevant to the inhibition of TSLP. That study's ongoing. We will be able to validate that side of the bispecific as well in the near future.
How might CDX-622 allow for a potentially even safer profile given its specificity?
Yeah. The uniqueness about our bispecific program in CDX-622 is our lead molecule in that is that we are targeting the ligand for KIT stem cell factor, as opposed to directly targeting KIT. The KIT receptor can be activated either by a soluble form of stem cell factor or a membrane-bound form of stem cell factor. These have different functions depending on which KIT-related function we're talking about. Mast cells primarily rely on soluble stem cell factor-mediated KIT activation for their survival. Whereas some other KIT-related functions that we talk about, like hematopoiesis, melanogenesis or pigment formation, and spermatogenesis, are thought to be more dependent on membrane SCF. We selected an antibody in CDX-622 in our follow-on products that really targets the soluble form of SCF, and we believe this will be more selective at inhibiting KIT and mast cells as opposed to systemic KIT inhibition.
How do you envision using CDX-622 and barzolvolimab hand in hand in deciding which indications to go after in the future for each of these assets?
Yeah. Well, these are very unique assets. We have learned a lot about the role of mast cells from barzolvolimab. What we also know is that in many indications, mast cells are contributing to the pathology, but they're not really just the only driver. The whole concept behind our bispecific pipeline in CDX-622 is to combine mast cell inhibition with a second pathway, with inhibiting a second pathway, in this case, the alarmin TSLP. We believe there are indications and specific patient populations that will be really well-served by targeting both of these pathways independent of how we're going to be developing barzolvolimab.
What will be the balance as you potentially become a near-term commercial story, but also building the pipeline and further testing this hypothesis to where mast cells may play a key role?
Well, if you're asking me.
He'll take the science.
I'll take the—w ell, I think Celldex has always been committed to continuing to develop the pipeline a nd advance innovative therapies. And so obviously in my role, that is a lot of my responsibility as we grow the company to be a commercial success.
Yeah. And we have been very clear with our investors that we want to be a commercial company, but we are going to continue to develop drugs. A fully integrated company is a company that has products on the market that we can market and bring in revenue. But also, we want to continue to be that leader in the mast cell biology space. And certainly Tibor and his team have brought some other programs forward, and Teri and her team are going to be responsible for marketing barzolvolimab. But obviously, she is going to market other drugs down the road.
Sometimes when that question is asked, it is as if those two things are at odds, and in fact, they are quite synergistic.
Yeah.
When we think about recruiting our commercial team, field team, building relationships with payers, having both, obviously near term or commercialized drug plus a pipeline, it strengthens our commercial positioning even long before that future pipeline is fully brought to market.
Yeah. I think, having that dual operation, it strengthens everybody's work inside the company. People appreciate the work other people are doing. It really focuses them in on, "Hey, we're developing these drugs to get to market." Whereas if you're in some other companies, there's really no sense of urgency or sense of timeline. Here, it's a professionally run organization, and the scientists and the business people certainly work hand in hand and really respect what each other does.
What do you think is the most misunderstood or undervalued component to your valuation?
Just when we first started the whole program with barzolvolimab, it is the safety issues around targeting KIT. I think that we are doing a nice job, especially over the last several years, of bringing those things to the surface. But at the end of the day, data is going to tell you everything. I think our data speaks for itself, and we look forward to flipping that card soon and getting ready to put this drug onto the market.
I might add the severity, the burden of this disease, and the significance of the unmet need, I do think is underappreciated.
Well, thank you so much.
Thank you. Appreciate it.
Wishing you all the best into these data in the next few weeks.
Thank you. Thank you guys for showing up today.
Thank you.