Celldex Therapeutics, Inc. Stock

Good day, and thank you for standing by. Welcome to the Celldex Therapeutics webcast. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your speaker today, Sarah Cavanaugh. Please go ahead.

Thank you. Good morning, and thank you for joining us. We're very excited to start our day discussing positive top line results from our 2 Phase III studies in chronic spontaneous urticaria, EMBARQ-CSU1 and EMBARQ-CSU2. In addition to being available on the webcast portal, the accompanying slides for this morning's call are also on the Investor Relations page of our website in the Events section. Joining me on the call this morning are Anthony Marucci, Co-Founder, President and Chief Executive Officer; Dr. Tibor Keler, Co-Founder, Executive Vice President and Chief Scientific Officer; Dr. Diane Young, Senior Vice President and Chief Medical Officer; Teri Lawver, Senior Vice President and Chief Commercial Officer; Dr. Margo Heath-Chiozzi, Senior Vice President of Regulatory Affairs and Quality; and Dr. Diego Alvarado, Vice President of Research.

Before we begin our discussion on this top line data, I would like to direct your attention to Slide 2 with respect to important information regarding the forward-looking statements that today's speakers will be making. We will hold a question-and-answer period after the presentation of the data. I would also like to note that these are very large studies encompassing almost 2,000 treated patients, and we received results very recently. The team has worked very hard to analyze the key data, and you will find today's discussion fulsome. That said, we are continuing to review data, and there will likely be questions we are unable to answer at this time. We look forward to presenting the full 24-week data set, which we intend to submit for presentation to the American Academy of Allergy, Asthma & Immunology Annual Meeting in February.

With that, we will now advance to Slide 3, and I will turn the call over to Anthony.

Thank you, Sarah, and good morning, everyone. For decades, we have seen well-controlled disease accepted as an adequate outcome in CSU. Today, we are incredibly pleased to share Phase III top line data that clearly demonstrate that barzolvolimab can do better for patients.

Turning to Slide 4. The data we are able to share with you this morning deliver on barzolvolimab's potential to be a transformational therapy for patients with CSU. Once again, this time across 2 studies comprising of nearly 2,000 patients from more than 500 sites in 43 countries. The primary endpoint and all key secondary endpoints have been met at both barzolvolimab dose levels. Across each endpoint, the data are clinically meaningful and demonstrate highly statistical significant decreases in disease activity.

We are seeing rapid, profound and durable efficacy that is best in disease in CSU. This deep efficacy continues to be clearly demonstrated in patients with the highest level of disease burden, severe disease that is refractory to omalizumab and CSU that presents with severe angioedema, uniquely positioning and differentiating barzolvolimab. While we are primarily going to show you efficacy at 12 weeks today, we saw in Phase II, these effects are sustained or deepened from week 12 to week 24 across all primary and key secondary endpoints.

Our overall safety profile through 24 weeks also remains consistent with our Phase II experience, now in a much larger diverse patient population. We have dosed about 2,400 patients with subcutaneous barzolvolimab across our Phase II and Phase III reported studies, delivering more than 11,000 individual doses of either barzolvolimab 150 or 300 milligrams in our Phase III studies alone to date. Our large Phase III experience reinforces that barzolvolimab has a predictable, consistent well-tolerated safety profile that we believe results in a favorable benefit to risk profile that will support barzolvolimab's broad use across CSU. We couldn't be more excited about these data and what it means for patients and physicians.

To remind you on Slide 5, CSU is a miserable disease that affects 1.8 million people in the U.S. alone. These people experience relentless, unpredictable hives, itch and disfiguring swelling that affects all aspects of their lives, including sleep and mental health. With barzolvolimab, we believe we have developed a highly differentiated medicine of choice for patients with CSU with the unique mechanism of mast cell depletion that directly targets the root cause of CSU. This mechanism is directly tied to the profound clinical benefit patients experienced. We look forward to completing the Phase III study while we are actively preparing for a BLA submission in 2027 and potential commercialization.

With that, I will ask Diane to talk you through the data. Diane?

Thank you, Anthony. I want to echo Anthony's comments. These robust data continue to reinforce that barzolvolimab with its unique mechanism of action has the potential to redefine the CSU treatment landscape. It's been 7 years since barzolvolimab first entered the clinic, and this rapid development would not have been possible without the support of the CSU community, especially patients, investigators and study coordinators. Their enthusiasm for and dedication to the barzolvolimab program is the reason why we are so excited to share these data with you today.

Turning to Slide 6. Let's review the trial design. The Phase III program is designed to establish the efficacy and safety of barzolvolimab in adult patients with CSU who remain symptomatic despite H1 antihistamine treatment. Both Phase III trials are randomized, double-blind, placebo-controlled parallel group global studies. 1,939 patients, 963 in EMBARQ-CSU1 and 976 in EMBARQ-CSU2, were randomized evenly to barzolvolimab 150 milligrams every 4 weeks following a 300-milligram loading dose, barzolvolimab 300 milligrams every 8 weeks following a 450-milligram loading dose or placebo for 24 weeks, at which point, patients on placebo were re-randomized to active treatment across both dosing groups. 1,935 patients were ultimately treated on study and 1,634 or 84% of patients completed the 24-week placebo-controlled treatment period.

The total treatment period is 52 weeks. As such, this is an ongoing study and remains blinded until completed. A Phase IIIb long-term extension study, or LTE, is ongoing, which patients can enter following completion of the Phase III trials. The primary endpoint of the study evaluates the clinical effect of barzolvolimab in reducing urticaria activity, weekly urticaria activity score or UAS7 at week 12. The study is designed to detect a clinically meaningful difference between each of the active arms versus placebo in the overall population as well as in the subpopulation of omalizumab refractory patients. The primary endpoint analysis was performed when all patients completed the placebo-controlled portion of the study at 24 weeks. The study was 90% powered to detect at least a 10-point difference between each of the active arms versus placebo in the overall population as well as in the subpopulation of omalizumab refractory patients. The key secondary endpoints are listed on the right-hand side of this slide, and we will review these in more detail shortly.

Slide 7 shows the demographic and baseline characteristics of the patients we enrolled into this study. Both studies are very well balanced across all arms and enrolled a diverse patient population with severe disease. As seen in our prior studies, roughly 2/3 of our patient population had severe CSU as demonstrated by a mean UAS7 score greater than or equal to 28 at baseline. They also had very high rates of angioedema. The Dermatology Life Quality Index indicates a severe population with mean scores of 14 to 16. The DLQI is a validated tool that measures the impact of CSU on daily life, indicating that their CSU had a very large impact on their quality of life. Across the 2 studies, 288 patients were enrolled who were refractory to omalizumab, representing approximately 16% of patients in CSU1 and 13% of patients in CSU2.

Turning to Slide 8. We are excited to dive into the efficacy results with you now. On Slide 9, let's look at the primary endpoint, mean change from baseline in urticaria activity score over 7 days at week 12. UAS7 is a patient-reported outcome tool. Patients record their daily itch and hive severity, which is totaled every week. We observed profound decreases with barzolvolimab treatment in UAS7 at week 12. Both barzolvolimab doses are clearly separated from placebo in both trials. The results are clinically meaningful and highly statistically significant with mean decreases of about 20 points on barzolvolimab compared to 10 points in the placebo group with comparisons having p-values less than 0.00001.

As we saw in Phase II, the primary endpoint result is strongly supported by positive data across all key secondary endpoints shown here on Slide 10. For the purposes of today's top line results, we are going to share the data across the 3 secondary endpoints we believe are of highest importance to patients and physicians and reflect the greatest unmet needs with current CSU therapies. The proportion of all patients with complete response, or UAS7 equal to 0, complete response rates in the subset of patients with disease refractory to omalizumab, and the proportion of patients who had no angioedema symptoms at week 12 as demonstrated by an AAS7 score of 0 in the subset of patients who had angioedema at baseline.

While we will not review the other key secondary endpoints today in detail, all were clinically meaningful and met high statistical significance. Importantly, this efficacy was sustained or deepened from week 12 to 24 across the primary and all key secondary endpoints. We also note that DLQI is not a key secondary endpoint in this trial, but we know that quality of life is important to patients and physicians. We look forward to sharing data on these secondary endpoints early next year at an upcoming scientific conference that reinforces the profound benefit barzolvolimab can have on quality of life.

First, on Slide 11, let's talk about what matters most to patients and physicians, complete response. As a reminder, complete response, measured by UAS7 equal 0, indicates the complete absence of itch and hives. Given the importance of this endpoint to patients and physicians and barzolvolimab's unique ability to drive sustained complete response, we are showing you this data at both 12 and 24 weeks. The difference compared to placebo is striking, and by week 12, up to 46% of patients have a complete response, which deepens to up to 54% by week 24. Consistent with Phase II, barzolvolimab offers complete response levels that are unprecedented in CSU.

Importantly, this profound efficacy is also demonstrated in the patient populations with greatest unmet need, patients with disease refractory to omalizumab and patients who have angioedema. The proportion of omalizumab refractory patients with complete response at week 12 is shown on Slide 12. Our definition of omalizumab refractory is very strict. Patients who were treated with omalizumab at approved doses for at least 3 months and whose symptoms never responded, who responded initially, but their symptoms subsequently returned or patients who discontinued omalizumab due to intolerance.

Again, even with this very high bar, we see results consistent with what is seen in the overall patient population with clinically meaningful and statistically significant separation from placebo. As is consistent with our mechanism of action, we know that barzolvolimab tackles the root cause of CSU, and we believe it should have broad applicability across all patient populations. Up to 55% of patients with CSU refractory to omalizumab experienced complete response at 12 weeks. These 2 studies are the first Phase III studies to demonstrate efficacy in the omalizumab refractory CSU population, a major advancement in the field.

On Slide 13, we show the profound benefit for patients with angioedema. Angioedema is marked by painful, deep and disfiguring swelling beneath the skin, most commonly on the lips, eyelids, face, hands, feet or genitals. Angioedema is significantly correlated with higher disease burden, and we believe that barzolvolimab has the potential to set a new standard in angioedema control, as shown here. We see clinically meaningful and statistically significant separation from placebo. Up to 74% of patients with angioedema at baseline achieved complete angioedema control at week 12 on barzolvolimab. As we have now seen across multiple studies in CSU, it is clear that targeting the root cause of the disease yields profound clinical benefit, offering new hope for patients and physicians who need better therapies for this miserable disease. The profound clinical activity demonstrated across the Phase III program is supported by a well-tolerated safety profile that is consistent with our Phase II barzolvolimab experience.

Turning to Slide 14. Let's review safety results from the trials. As shown on Slide 15, the combined placebo-controlled safety data set includes almost 2,000 patients observed for 24 weeks. As a standard practice for clinical trials, in Phase II, we reported adverse events observed in 10% of patients or greater. For Phase III studies, you typically report AEs observed in greater than 3% to 5% of patients. For the purposes of this analysis, we are reporting a 3% cutoff. Barzolvolimab showed favorable safety consistent with prior experience. There were no new meaningful safety signals identified. Across the study on barzolvolimab, the vast majority of adverse events observed were mild to moderate, and the most common adverse events are KIT-mediated and expected to be reversible as we have demonstrated in our Phase II CSU study. The rate of serious events was balanced between placebo and the barzolvolimab arms.

I will provide a brief summary of the serious adverse events reported as treatment related, which can be attributed to either barzolvolimab or placebo. There were 2 cases of anaphylaxis following the first dose of barzolvolimab administration adjudicated by a blinded, independent expert committee as probable. The symptoms occurred shortly after dosing and the patients made a full recovery. A single case of anaphylaxis, adjudicated as probable, occurred following the first dose of placebo in the 300-milligram barzolvolimab Q8-week arm.

As a reminder of our protocol, to maintain blinding for patients in the 300-milligram Q8-week cohort, patients received placebo on alternating visits to match the dosing frequency of the 150-milligram Q4-week arm. This patient tolerated their first barzol dose well and then 4 weeks later, immediately following their first placebo dose, experienced symptoms. The adjudication committee deemed this probable based on the acuteness of the event immediately following blinded placebo treatment.

There were 5 other treatment-related serious adverse events on the 2 studies. A patient in the placebo arm experienced symptoms after the first placebo dose reported as Grade 3 anaphylaxis, which was adjudicated as unlikely. The patient discontinued treatment. In the 150-milligram arm, 1 patient reported Grade 2 urticaria, angioedema and throat tightness and did not seek medical attention. The patient discontinued treatment. This potential hypersensitivity event was sent to the adjudication committee and deemed to be consistent with their underlying disease.

In the 300-milligram arm, 1 patient experienced Grade 3 anemia and neutropenia that was not associated with infections. Treatment was discontinued and they fully recovered with barzolvolimab on board. In the 300-milligram arm, 1 patient experienced a single Grade 2 event of malaise, chest pain and shortness of breath, recovered, and continues on treatment. A patient experienced symptoms reported as Grade 3 anaphylaxis, adjudicated to be unlikely, which occurred following the third dose of placebo in the 300-milligram barzolvolimab Q8-week cohort.

To be clear, there were 2 adjudicated cases of probable anaphylaxis following barzolvolimab treatment across both Phase III studies. To date, these 2 adjudicated cases are the only cases observed across the entire barzolvolimab subcutaneous program, including ongoing studies in AD, SD and ColdU, representing more than 2,400 barzolvolimab-treated patients. This is well in line with what you would expect to see with injectable biologics.

On Slide 16, we are very pleased to see in this robust Phase III study that the results indicate that treatment with barzolvolimab did not lead to increased rate of infections, and there was no association between neutropenia and infection. Most importantly, the rates of infection were balanced across placebo and barzolvolimab-treated patient groups, including the rates of serious infections. This supports that barzolvolimab did not lead to increased infections. Rates of neutropenia are consistent with Phase II, 9.1% of patients on the 150-milligram arm and 11.7% of patients on the 300-milligram arm experienced an adverse event reported as neutropenia. These events were mostly mild to moderate.

To summarize, the safety observations from 24 weeks of placebo-controlled treatment in almost 2,000 patients are consistent with the favorable safety profile we observed throughout this program. The safety profile primarily reflects that the mechanism-related adverse events are generally mild and without clinical sequelae and are expected to be fully reversible. We believe the safety profile, combined with the unprecedented efficacy, results in a highly favorable benefit to risk profile. Results support our plan to submit a BLA in 2027, and we are making great progress on CMC and other supporting activities required for a successful submission.

Turning to Slide 17. I will now pass the call over to Teri to talk about the opportunity to bring barzolvolimab to patients as we plan for commercialization. Teri?

Thank you, Diane. Let's turn to Slide 18. With these exceptional results, I want to describe how we see the potential for barzolvolimab to uniquely address large CSU patient populations with significant unmet needs. We have heard time and time again from the CSU community that they are looking for more than just improvement. They aspire to be completely free from their symptoms and the anxiety associated with not knowing when the next flare might occur. In these top line results, we see barzolvolimab's potential to address these needs.

Here, we illustrate where we see barzolvolimab fitting into the evolving CSU treatment paradigm, addressing 2 large CSU populations with significant unmet need. First, we see barzolvolimab as a potential first-line advanced therapy of choice for patients presenting with severe disease or with severe angioedema. Earlier, Diane reviewed the exceptional EMBARQ-CSU results in delivering both new UAS7 equals 0, meaning complete control of disease in up to 54% of patients at week 24 and AAS7 equals 0 or complete control of angioedema in up to 74% of patients at week 12.

As a reminder, more than 2/3 of patients in our EMBARQ-CSU Phase III program were experiencing angioedema at baseline with mean AAS scores at baseline over 50, indicating severe angioedema. Currently, there are no approved CSU therapies with labeling demonstrating angioedema control. Drawing your attention to the right of this page, we also believe that barzolvolimab has the potential to be the therapy of choice for second-line advanced CSU treatment in patients who remain symptomatic after treatment with any one of the currently approved therapies. Diane previously shared a profound complete response measured as UAS7 equal 0 in up to 55% of patients at week 12 whose disease is refractory to omalizumab. Currently, there are no approved CSU therapies with labeling supporting use in advanced therapy refractory CSU.

Turning to Slide 19. I want to reiterate how thrilled we are with today's results as they establish a strong foundation and prepare us well for potential commercial success. Barzolvolimab is a unique, novel, first and only-in-class antibody with the potential to deliver efficacy that is highly differentiated on the endpoints most important to CSU patients and their health care professionals. Today's positive Phase III readout amplifies our excitement about the transformational impact barzolvolimab can have for patients and reinforces our confidence in the significant potential of this novel therapy. We remain fully focused on bringing barzolvolimab to patients as expeditiously as possible and on executing a streamlined and robust launch strategy that is fitting of this innovative therapy.

With that, I will turn it back to Anthony to wrap up. Anthony?

Thank you, Teri. Let's turn to Slide 20. We are incredibly proud of our progress and execution over the past 7 years, delivering on our leadership in mast cell biology and bringing barzolvolimab through to Phase III. Today's results mark the next phase of the journey of bringing people with CSU what we believe to be life-changing therapy. These results are unprecedented and offer new hope for patients, physicians and the CSU community.

As demonstrated across the life of barzolvolimab program and reinforced in Phase III, suppressing KIT with barzolvolimab targets the root cause of CSU and leads to rapid, profound and durable efficacy. The favorable safety profile is also highly consistent with what we've observed in the past experience, which we are incredibly pleased with these large nearly 2,000-patient trials. We continue to work on bringing this important medicine to patients and are focused on completing the EMBARQ-CSU studies and preparing for BLA submission in 2027.

As mentioned by Sarah earlier, we plan to submit the 24-week data from the EMBARQ-CSU trials for presentation at Quad AI in February. We also look forward to sharing more about barzolvolimab's potential in additional indications in the near future. We plan to report the Phase II atopic dermatitis results in the fourth quarter of this year, and our Phase III SD and ColdU trials are on track.

To conclude, I'd like to thank everyone for your support in our barzolvolimab program, especially the patients, and we are excited about the next phase as we prepare to become a commercial stage organization. Thank you for joining us. Before I turn the call back to the operator and opening up the call for questions, I would like to remind you that this is an incredibly large data set, representing nearly 2,000 patients, and we have only recently received it. We are thrilled with the results and want to share them as quickly as possible and also want to remind you that we may not be able to answer questions on every question you may have at this time.

Operator, please open the call.

[Operator Instructions] Our first question comes from the line of Tom Smith with Leerink Partners.

This is Nat Charoensook on for Tom Smith. Congrats on the data, and we have a few questions. So the first one on the onset of efficacy, how quickly did you see responses? And how consistent was the experience between omal-naive and omal-refractory patients? And I have a few follow-ups.

So we see -- we have rapid responses in these studies. We are going to present more about that data at the Quad AI next year. We're very pleased with the rapidity of response that we have.

We're still going through the data. We know we see it as early as 2 weeks. We're looking to see if we see it even earlier, but it's very rapid, as we said. And again, we're going through all the data now. But at 2 weeks at minimum, maybe even faster as we go through the data.

Got it. And in the 2 adjudicated cases of anaphylaxis, can you elaborate more on the clinical course for these patients? Like was there any additional background that could have contributed to this? And were there any commonalities between these patients that might allow for identification of patients that are at greater risk for anaphylaxis?

Yes. So as we described, we have 2 cases of confirmed anaphylaxis following administration of barzol across the whole program. These 2 cases were adjudicated by an independent anaphylaxis adjudication committee. In both of these cases, the onset of symptoms was rapid. In one patient, it was 10 minutes and the other it was 2.5 hours. One patient was actually had hospitalization. The other one was just treated in the clinic and discharged, so less severe. So -- but they were both felt to be probable anaphylaxis by the adjudication...

Got it. Very helpful. And have you looked at the exposure-adjusted rate of anaphylaxis for this subcu of barzolvolimab? And how does this compare to other biologics that are approved to treat allergic conditions?

We have not looked at the exposure-adjusted rates at this time with that data we're going to get later.

But at this point, we have 2 cases out of 2,400 patients, which compares very favorably with other biologics.

Got it. And last question. What are the discontinuation rates observed for these study arms? Can you give, like, a brief comment on that?

Yes. So the overall discontinuation rate from the placebo-controlled period was 16%. The main reasons for discontinuation were withdrawal of consent by patients as well as adverse events.

Our next question comes from the line of Yaron Werber with TD Cowen.

Great. So maybe just a quick question. It looks like the serious adverse events are pretty much identical in the barzol arm to placebo at 1% to 2%. I just want to make sure is that correct? And can you give us a sense -- yes, go ahead.

No, no, I was just going to say that the rates of serious adverse events are similar between the barzol treated groups and the placebo group.

And so that's super encouraging. The -- when you're looking at the Grade 3 and 4, I mean, you're calling some of them in Slide 15. Is there anything else that's worthwhile for us to keep in mind with that respect?

Yes. No, there was also -- there was no increase in Grade 3, Grade 4 adverse events on barzolvolimab versus placebo across the study.

Okay. Amazing. And when you look at skin hypopigmentation, it looks like there were both cases of hyper and hypo, they're all sort of around 10% versus kind of low single. Anything specific worth calling out there? Congrats on the data. It looks really good.

Thank you. So hypopigmentation, we've described before, and we really see similar picture here. Hyperpigmentation shows up here. We actually have seen that previously. We saw that in our Phase II studies of CSU and CIndU. The rate was about 4% in those studies. So it didn't make it to our based on the 10% cutoff. But we do know from the Phase II data that those cases are mostly mild. They were reversing. And we do believe it's a KIT-mediated effect because similar events were reported on imatinib therapy.

And then maybe just a final question. Even in patients who discontinue in the study because we know from your previous data that efficacy is fairly durable, would you still look at their efficacy over time?

We will look at the efficacy in the patients who discontinue the study. We haven't gotten to that yet, but we will do that.

We expect to see similar numbers, Yaron.

Our next question comes from the line of Yatin Suneja with Guggenheim.

Congratulations on very good results. I mean, obviously, the Street is a little bit more focused or investors a little bit more focused on the safety side today. So a quick clarification. So it seems to us that you only have just 2 cases of anaphylaxis out of these 2,400 patients. So the percentage is much lower than what we see with many biologics. So the question is, what do you think is the implication for the label, if any? And the reason I ask is that because some of these widely used drugs like even Dupixent have anaphylaxis and warning section -- and warning flagged on the label. So is that going to be anything different for you? So that sort of is the first question, and then I have a follow-up.

Yes. So as we discussed, we have 2 adjudicated cases following the administration of barzol across the entirety of our subcutaneous program, which is about 2,400 patients, and these occurred immediately following the first barzolvolimab dose. As we said previously, and the data support it, we believe that we will have a label consistent with other biologics. That is something in the warning precaution section for hypersensitivity and anaphylaxis.

Any biologic with the exception of Xolair and Teva's drug have similar warning labels for hypersensitivity and anaphylaxis. And as you know, we've been saying that to people for the last 4 or 5 years. So these data are extremely encouraging and 2 out of 2,400 is well within the range of acceptability.

Got it. Very good. Then just one follow-up on the angioedema benefit that you're seeing. Could you talk about the baseline severity of these patients, specifically on angioedema? I mean, I think that's where you also differentiate because I don't know if any other drug has shown that level of benefit on angioedema. So I would love to understand how that is.

Sure. So just like in the Phase II study, the baseline was pretty high. A number of them came in with severe disease. And these data are replicating the Phase II experience what we're seeing. Very severe patients coming in. The differential between us, our drug and the placebo patients is obviously statistically significant and much better than what you would experience with other drugs out there. So on par.

This is Teri. I might add 2 things. One is the placebo delta on these results is the best that's been seen by far with any CSU medicine in any publication. And a reminder of the correlation between the incredibly high burden of disease that comes with angioedema. So these results really speak to the overall impact of these results.

Our next question comes from the line of Kristen Kluska with Cantor.

Huge congratulations on these data set, very impressive. So you mentioned of the 2,400 patients on therapy. Can you just clarify if that includes all studies to date, including other ones that are currently up and running? And just given that it seems that these 2 cases reported today and the one in PN for anaphylaxis occurred on the very first dose, is there also a case to be made that maybe just if certain physicians are higher risk, they'll just administer the first dose in office?

Sure. So yes, it is across all current and studies done in subcutaneous. That would include the AD study, that would include the ongoing Phase III SD and ColdU studies.

And we do agree that these 2 cases occurred after the first dose as well as the IV case you mentioned.

Kristen, HCP in-office administration is the base case for the launch, and we continue to plan for an auto-injector with at-home administration roughly 18 months post initial approval.

Okay. And then, Teri, you've talked about the 2 different patient segments where you think you could have the highest unmet need where barzol could be attractive. Of the roughly 500,000 or so, what percent or number of patients do you think are applicable to each of the categories?

Yes. In the first line with severe or angioedema, so we know that 55% of patients overall present with angioedema. There are no published data on the percent of that breakdown of mild, moderate to severe, but the best data that we have access to tells us that up to 1/3 of those with angioedema are categorized as severe angioedema. And then you can see here on the slide, 25% to 30% of patients with CSU presenting severe. When we look at the overlap, the intersection of those 2, Kristen, we estimate that at about 20% of first-line patients for barzolvolimab is uniquely positioned with its clinical profile to be the potential therapy of choice.

On the second-line data, this is very much evolving. There was no second-line advanced CSU therapy until just 18 months ago. We do see that number growing. And the trajectory that we see along with the analogs we've seen in other I&I diseases would project that the second-line advanced therapy market would eclipse the first-line advanced therapy market within the first 2 years of the barzolvolimab launch.

Our next question comes from the line of Sam Slutsky with LifeSci Capital.

Congrats on a positive update. I guess 2 for me. One, as you kind of move towards commercialization, could you talk about the build-out as you're thinking about sales reps ex U.S. versus U.S. plans and then kind of what has to be done between now and then? And then just a quick clarification. I think I heard you mention 16% dropouts due to AEs. Do you know what the rate was kind of between arms? And then was there anything driving it? Or was it pretty dispersed across AEs?

I'll answer the AE question first. So there was a 16% overall dropout rate in the study. The dropout rate related to AEs was more like 8%. And then the most common ones were the low rates that were hair color, skin pigment changes and neutropenia. And it's really very consistent with what we've seen in our previous studies.

Sam, let me address your question about the commercial build-out. Obviously, first, look, these results are unequivocal and give us great confidence in the commercial strategy that we've been discussing for the last several months. In terms of our field team, we will build a competitive, appropriately sized field team. We know, based on the data and we're collecting all of the available public data tracking it monthly. We know exactly who are the HCPs who are prescribing advanced therapy. And our field footprint plan is to be present with a competitive presence in all of the offices where advanced therapy is being prescribed. You also asked about our OUS plan.

Yes. So Sam, obviously, the U.S. plans, we're going to look and consider several things, including the future indications, future pipeline, and we're looking at the regulatory and policy environment as we go on. So we're looking at all of those things to move forward. And once we get a little bit more clarity, we can give you a better update down the road.

Our next question comes from the line of Judah Frommer with Morgan Stanley.

Congrats on the data. Maybe first, and I apologize if I missed it, but what are your thoughts on commercialization of both doses? Could you potentially see pushing the every 8-week dose that did not have the anaphylaxis? Could there be kind of different prescribing patterns with one versus the other given the safety profile?

Thank you for the question. We see a very strong and consistent efficacy and safety across both doses that giving us optionality. We see there are certain patients and certain HCPs who like the consistency of the potential for every 4-week therapy, which is a very manageable dosing regimen. And we know that there are patients and physicians who would prefer less frequent dosing. That Q8-week dosing, 300 mg Q8-week, gives us a very nice potential competitive advantage in terms of frequency. It gives -- provides the potential for 7 days per year of treatment, which is best-in-class for any CSU therapy. So we really like the consistency and the optionality, and we'll seek the opportunity to present that optionality in the label.

Yes. And also, remember, we had the cases at 150 and the placebo was at 300. The other 2 cases that were adjudicated unlikely to be anaphylaxis were both placebo as well. So we don't think it's anything with the 150 or the 300 because as you can see, even patients that got placebo had reactions as well.

Got it. Okay. And then just on the hair color changes numerically, those rates look higher than the Phase II. And I don't think there were any placebo hair color changes in the Phase II. Was there any change in the assay or the investigation on hair color changes between Phase II and Phase III?

Yes. So the hair color changes, as we've said, hair color changes are really expected in the study. It's a KIT-mediated effect. It's mild, it's reversible. So we expect hair color changes in the study. A couple of things to note here is that we have longer follow-up in this study. So we -- this is a 24-week placebo-controlled period as opposed to some other earlier studies with shorter follow-up intervals.

But I would say that there's greater -- much greater awareness of hair color changes. We are looking for them in the study. We talk about it in informed consent. The investigators are all aware. So I think people are looking for these things. And we do, in fact, see -- as you mentioned, see all these KIT-mediated effects now in placebo. And I think that's the nature of it, it can be kind of a subtle finding and people are more aware, so they're calling it. But it's really just reports of patients and investigators.

And Judah, remember also, this is a population that the mean is in the late 40s. So you're expecting to see hair lightening, and that's why you're seeing it also in the placebo. But remember, from the time we started this program in Phase I, we were looking for these KIT-mediated on-target effects: hypopigmentation, hair color changes, all these things were part of the history of targeting KIT.

And as we're learning through clinical development, these are the things that we want to learn. We're not going to shy away from them. But obviously, they have no clinical benefit -- I mean, risk. They're completely reversible as we have seen in our Phase II, and we'll show it again as the patients go through the Phase III program that these are completely reversible and have no clinical impact whatsoever.

Our next question comes from the line of Derek Archila with Wells Fargo.

Congrats on the data. So just 2 questions. Is it your intent to file for approval of both doses of barzol? Or is there a case to pursue just one? And then the second question is, just remind us whether you need any longer-term data from this study prior to filing the BLA.

Margo, can you answer both doses for Derek?

Yes. We intentionally set out to characterize both doses because we'd like to offer patients optionality. And since the data looks so consistent across them, we will certainly want to support that, that's an appropriate way of using the product. On the -- what else are we going to need, we have been aligned with the agency throughout the development. And so we're certainly going to share this data and then align with them on how to get this drug to patients as quickly as possible. So we want to share with them where we are, and then we're going to align with them on where to go.

Maybe just a follow-up there. I guess the question is really, do you need any like longer-term data? Do you need to show like 52-week data from the study or any additional safety?

Well, I mean, this is the 24-week cut with then ongoing data coming in as we're going. So we fully anticipate having -- I mean, these were large studies. So we have a lot of data. And so we'll be talking -- we don't know -- I don't have a crystal ball in terms of what magnitude, but we certainly will be sharing with them how this large data set is emerging.

No, I was going to say we already have over 500 patients treated out to a year. So whatever the FDA needs, we're close.

Our next question comes from the line of Alex Thompson with Stifel.

I guess another one on dosing and thoughts about the label moving forward. How are you thinking about the addition of the loading dose here relative to Phase II? What does it seem to be beneficial relative to your expectations in terms of clinical efficacy? Is that something that might be up for discussion with FDA, especially when you think about safety profile here? And then when you're thinking about positioning as a second-line option, as with other I&I markets, should we expect premium pricing here relative to some of the first-line comps that are out there?

Yes. So let's take the first part with Tibor and then Teri can answer the other part.

So we believe the loading doses are helpful. We still have data to analyze here. But overall, we certainly don't believe they've contributed at all to a difference in the AE profile. We think our profile in Phase III is very consistent with what we had in Phase II. Again, our loading doses are modest. They're just intended to get patients into the level of KIT saturation more rapidly by giving this loading dose. Again, we'll look at the data more carefully, but we think that certainly, we know that rapid response is important to patients, and we think these doses have clearly a good safety profile. And I would expect that we will use the loading dose as part of our regimen in the commercial approach.

Yes. And Alex, just to level set everything here. So if you remember in the Phase II, the 300 dose was below the 51% that we saw at 150. It was around 37.5. And we saw that at the 6- to 8-week time frame, the 300 was coming back a little bit. So in this -- we saw, what, a 44% blended rate of response in the Phase II study. So when you look at the rates now, the 300 and the 150 are fairly close. So we think that the loading dose was helpful here to the point where 44.25 was the blended rate in Phase II and then the Phase III rate was 43.6. So the word that keeps coming up with us is consistency on all the data here, and this was the same here.

Teri, you want to answer that question on pricing?

Sure, Alex, on your pricing question, we do believe a substantial differentiation of the overall profile as well as the differentiation in important patient populations that other therapies cannot adequately address. That combination of factors, we do believe will translate into economic differentiation as well and will support a value-based premium pricing strategy.

Our next question comes from the line of Richard Law with Goldman Sachs.

This is Tolani Uthman on for Rich. Congrats on the results this morning. To follow up on the earlier label question, I wanted to ask, given -- sorry, given the emergence of the 2 anaphylaxis cases, do you anticipate any risk of a box warning? And if so, how do you anticipate that might impact commercial uptake?

No. So as we've said, we really believe that these data are really supporting a label, which is consistent with the other biologics out there, which is a warning that includes hypersensitivity, including anaphylaxis. And that's what is our expectation.

Yes. I mean, 2 out of 2,400 patients, do the math, it's extremely low. So we're very happy with it.

All right. And if I could drop in one more on commercial. How do you expect barzol will be used between chronic and intermittent use in a commercial setting based on the efficacy and safety profile you shared today?

CSU is a chronic disease, and this is a chronic therapy. That is how we anticipate the label and the intentionality for use.

Our next question comes from the line of Andy Chen with Wolfe Research.

This is [ Jason ] taking in for Andy. We just want to ask about the neutropenia. So the overall infection rate looks good, but could you break out the infection outcomes specifically among patients who develop neutropenia? And specifically, do those patients have more opportunistic infections or generally more severe infections compared to placebo? And are there any trend of treatment time increasing with infection risk/rate?

So we have absolute consistency in terms of similarity of rates of infections and serious infections across placebo and barzolvolimab-treated groups here, including serious infections. We do not see an association of infections with neutropenia. In terms of the infections, we do not see opportunistic infections. There's really nothing in this data that indicates any sort of infection signal.

Our next question comes from the line of Etzer Darout with Barclays.

This is Gustave on for Etzer. Congratulations on the data. At launch, what do you think will be the biggest driver of physician adoption versus remi or dupi? Is it more the angioedema control, the efficacy in refractory patients...

I'm sorry. I'm sorry, you're coming off very muffled. Can you repeat that?

Yes. Can you hear me now?

Still a little muffled, but better. Go ahead.

Okay. All right. So what do you think will be the biggest driver of physician adoption versus remi or dupi? Is it the angioedema control, the efficacy you're seeing in refractory patients? What are your thoughts on that?

We see 2 very large patient cohorts with significant unmet need where barzolvolimab is uniquely positioned to address patient needs, and this is where we see the greatest adoption likelihood. The first is for first-line advanced therapy, so patients who have tried highest dose antihistamines are still experiencing active disease and who are presenting with either severe disease or severe angioedema or that combination. For reference on the size of that opportunity in our Phase II trials, and we're still in the process of calculating it for our Phase III. But in our Phase II trials, 36% of patients had both severe angioedema and severe CSU. So this is a very meaningful portion of the first-line advanced therapy population.

The second likely high adoption opportunity for barzolvolimab is as the treatment of choice for second-line advanced therapy. So this is for patients who have tried any one of the currently approved advanced therapies and are still experiencing symptoms. And as we've seen with other I&I biologics, we -- I&I categories, we would anticipate the second-line advanced therapy market, in fact, to eclipse the first-line advanced therapy market within the first few years of barzolvolimab's launch. As a reminder, there are no other approved CSU therapies with labeled indications demonstrating efficacy in a biologic refractory population.

Thank you. This concludes the question-and-answer session. I'd now like to hand the call back over to Anthony Marucci for closing remarks.

Thank you, operator. And I want to thank everybody for joining us this morning. We are extremely happy to be able to present our data set with you at 12 weeks. As we said, we will present the complete data set at Quad AI in February, and we are working hard to go through all the data that we have so far, but we are incredibly happy about our data. We want to thank the physicians, the patients, everyone who has supported us throughout this Phase III program. We've got this thing done in less than 7 years, which is extraordinary, and we continue to want to show you good data going forward. So we look forward to it, and have a good day. Thank you.

This concludes today's conference. Thank you for your participation. You may now disconnect.

Thank you for standing by, and welcome to Celldex's Phase II PN Data Call. [Operator Instructions] I would now like to hand the call over to Sarah Cavanaugh with Celldex. Please go ahead.

Thank you. Good afternoon, and thank you for joining us to discuss the results from our Phase II Barzolvolimab study in Prurigo Nodularis or PN. Joining me on the call today are Anthony Marucci, Co-Founder, President and Chief Executive Officer; Dr. Tibor Keler, Co-Founder, Executive Vice President and Chief Scientific Officer; Dr. Diane Young, Senior Vice President and Chief Medical Officer; and Teri Lawver, Senior Vice President and Chief Commercial Officer.

Please note the slides for today's call are available on the Investor Relations section of the website. Before we begin our discussion, I'd like to direct your attention to Slide 2 with respect to information regarding the forward-looking statements that today's speakers will be making. Please be advised that a question-and-answer period will be held later in this call. I'd now like to turn the call over to Anthony on Slide 3.

Thank you, Sarah, and good afternoon, everyone. Thank you for joining us. Today, we are reporting Barzol's results from our fourth indication, a Phase II study in Prurigo Nodularis or PN. PN is a chronic itch-driven skin condition with a highly symptomatic patient population. At Celldex, we are leading important science in the exploration of mast cell biology with the goal of delivering life-changing therapies for patients with allergic inflammatory and autoimmune diseases. We have repeatedly demonstrated Barzol's ability to profoundly deplete mast cells and best-in-disease data observed in 3 indications to date: Chronic Spontaneous Urticaria, Symptomatic Dermographism and Cold Urticaria.

All these showed unequivocal Phase II data and progressed quickly to Phase III development. Our interest in understanding if mast cell depletion can provide clinical relief for patients with serious diseases and data from our Phase I proof-of-concept study in PN supported the initiation of the Phase II study. We are disappointed to share that the trial did not meet the primary or secondary endpoints. Results from this study clearly showed profound systemic depletion of mast cells as evidenced by the reduction in serum tryptase. But unlike our intravenous Phase I study, this Phase II Subcu study did not result in improvements in itch or skin lesions for patients, indicating that mast cells may not be the key pathogenic driver of symptoms in PN.

Because of this outcome, we are discontinuing the Phase II trial in PN and will direct our resources to the remainder of our present and future portfolio. We remain focused on driving mast cell category creation and delivering on Barzolvolimab's promise for patients, particularly in our 3 ongoing Phase III Urticaria studies, which we expect to share top line data in the September, October time frame.

Before I turn the call over to Diane to walk you through the data, I'd like to extend our gratitude to all the patients, investigators and site staff around the world who participated in this trial and supported the advancement of mast cell science. Diane will walk you through the results we have to date. And at the end of the call tonight, we will answer as many questions as we can. As a reminder, this is a top line analysis with additional work still to be done. I will now hand the call over to Diane.

Thank you, Anthony. Before we review the data, let's spend a little time discussing this difficult-to-treat indication. Prurigo Nodularis is a chronic inflammatory disease. Patients are often covered with hard itchy skin lesions. The intense itching causes scratching to the point of bleeding and pain and the scratching in turn can cause more skin lesions perpetuating the disease cycle. PN is further complicated because it is often associated with a range of systemic comorbidities, including chronic kidney disease, metabolic disorders, HIV and tuberculosis infections, hepatic disorders and autoimmune diseases.

Patients with PN have also been shown to have increased rates of multiple cardiovascular comorbidities, including heart failure. Not surprisingly, given the relentless itching, patients frequently also exhibit psychiatric comorbidities such as depression, anxiety and obsessive compulsive disorder, further complicating management. While there has been progress in this space with the introduction of recently approved biologic therapies for Prurigo Nodularis, there is still a significant unmet need.

As we explored the science of chronic itch, it became increasingly clear that investigating a mast cell depleting agent was warranted in Prurigo Nodularis. Evidence indicated that mast cell interaction with sensory neurons is involved in the amplification of chronic itch and neuro-inflammation and could play an important role in the scratch itch cycle. Additionally, studies have shown that mast cell numbers are increased in PN lesions.

We conducted a small 23-patient Phase Ib study with intravenous Barzolvolimab and saw positive results across both itch reduction and nodule resolution at the highest dose tested, and that merited additional exploration in a robust Phase II study.

Turning to Slide 4. I will first walk you through the Phase II study design. This was a randomized, double-blind, placebo-controlled parallel group study that evaluated the efficacy and safety profile of 2 dose levels of Barzolvolimab administered subcutaneously compared to placebo in patients with moderate to severe PN who had inadequate response to prescription topical medications or for whom topical medications were medically inadvisable. 140 participants from 6 countries and 48 sites were randomly assigned on a 1:1:1 ratio to receive placebo or Barzolvolimab injections of either 150 milligrams or 300 milligrams every 4 weeks after an initial loading dose of 450 milligrams during a 24-week treatment phase.

Participants then entered a follow-up phase with no treatment for an additional 16 weeks through week 40 with an option to enter an open-label extension. The primary objective of this study was to evaluate the clinical effect of Barzolvolimab compared to placebo on itch response as measured by the proportion of participants with greater than 4-point improvement in the worst itch numeric rating scale at 12 weeks. Key secondary objectives include itch response compared to placebo at different time points, the assessment of skin lesions as measured by the investigator global assessment and safety. The primary analysis was conducted after all patients had completed the 24-week placebo-controlled treatment period.

On Slide 5, you will see a table of baseline characteristics for this highly symptomatic patient population. Demographics and baseline disease characteristics were generally well balanced across treatment groups and consistent with other clinical studies in PN. As expected in this indication, patients on study tended to be older and had highly symptomatic moderate to severe disease.

The next slide, Slide 6, shows the results for the primary endpoint, the percentage of patients who had greater than 4-point improvement in their worst itch numeric rating scale. The worst itch numeric rating scale is a single item patient-reported questionnaire that measures itch intensity over the previous 24 hours. The scale ranges from 0 indicating no itch to 10 indicating worst itch imaginable, and patients at this trial -- in this trial at baseline had a mean Worst Itch NRS score of greater than 8. As you can see here, patients treated with Barzolvolimab did not have differentiated responses compared to placebo across either dose or at any of the time points.

Similarly, on Slide 7, we show key secondary endpoints, including the investigator global assessment for chronic nodular prurigo stage, which is a 5-point clinical scale that dermatologists use to measure the severity of Prurigo Nodularis. It evaluates the number and appearance of palpable skin nodules to gauge disease severity. There is also a secondary endpoint that looks at both Worst Itch and investigator global assessment combined. Across these endpoints, Barzolvolimab did not demonstrate differentiation compared to placebo. Based on these outcomes, we are in the process of discontinuing the Phase II study in prurigo nodularis.

We just received these data, and we have more work to do to understand the discrepancy between our Phase Ib and Phase II studies in this indication. While the patient characteristics across the 2 studies were similar, the Phase II study certainly included a much larger sample size. The route of drug administration was also different from IV in the Phase Ib to subcu in the Phase II. IV administration is associated with more rapid and higher drug concentrations relative to subcu. We can't rule out that these differences may have contributed to the difference in outcome.

However, both studies achieved profound decreases in circulating tryptase. We have biopsy samples that may give us better insight. We will analyze the biopsies from this study in the coming months as we believe this information will increase our learnings. Our current assessment of the available data suggests that mast cells may not be a key pathogenic driver of symptoms in Prurigo Nodularis. And at this time, we are not planning to move forward with further development in PN. If new data or new science changes our thinking, we are open to exploring this question in the future, if it makes sense. For now, we are focusing on indications of higher priority.

While we are disappointed that this study did not confirm the promising signal we saw in our Phase Ib study, we are really pleased with these new data that further support the favorable safety profile we have observed to date with Barzolvolimab. The 450-milligram loading dose followed by the 300-milligram Q4-week dosing regimen achieved the highest subcutaneous exposure studied to date.

Slide 8 provides a summary of the top line safety data. Overall, Barzolvolimab was well tolerated. We are very pleased with the safety profile demonstrated in this Phase II study, which remains entirely consistent with our prior studies at these dose levels and in an older patient population with high comorbidity burden. As noted on the slide, there was a single serious adverse event reported by an investigator as treatment-related and described as aseptic meningitis. We strongly disagree with the investigator's assessment and our conclusion was also supported by the independent data monitoring committee. The clinical symptomatology does not support the investigator's assessment. There were no typical clinical signs suggested of this diagnosis such as headache, neck pain or fever.

This 65-year-old female patient had a primary complaint of chest pain and weakness, which began 3 weeks after completing her Barzolvolimab treatment. She had an extensive workup over a 4-week period, which ruled out cardiac, pulmonary and GI causes and subsequently, neurologic diagnoses were considered. Her cerebrospinal fluid showed mild lymphocytic infiltration with normal protein and glucose, which is not typical with meningitis. Steroids, antiviral therapy and antibiotics were administered and the patient made a full recovery.

We believe the time course, lack of symptoms and spinal fluid findings suggest this is more consistent with neuro-inflammation related to a viral infection and is not related to study drug. 11 patients, including 2 patients on placebo discontinued treatment due to an adverse event, 5 considered related to treatment and 6 considered unrelated. Urticaria related and worsening prurigo unrelated occurred in 2 patients each. The other events occurred in single patients and were in line with what has been seen in prior studies with one exception.

One death, cardiac failure, which was assessed as not related to treatment by the investigator sponsor and the data monitoring committee was reported on study. This was in a 73-year-old man with multiple concomitant cardiac risk factors at baseline, including diabetes, hypertension, obesity, coronary artery disease, heart failure, COPD and low baseline oxygen saturation. As a reminder, the PN population is an older population with high comorbidity burden and as such, it is not uncommon to see serious adverse events that are not related to treatment. When we look across the totality of the safety data in the study, we see a safety profile that is very much consistent with our other studies.

Looking to the bottom of the table, the most frequently reported adverse events observed in more than 10% of participants in any treatment group were hair color changes and nasopharyngitis, all of which were grade 1 and grade 2. Overall, we are encouraged by the consistent safety profile we have seen with Barzolvolimab in this trial where we explored the loading dose and 4-week dosing regimens. These data give us continued confidence in the overall safety profile and particularly the ongoing Phase III studies in CSU, ColdU and symptomatic dermographism, which also include the loading dose.

I will now hand the call back to Anthony, who will wrap things up. Anthony?

Thank you, Diane. Turning to Slide 9. While we are disappointed that the study did not confirm the promising signal that we observed in the Phase Ib, we are proud of our progress and continued execution. As leaders in mast cell biology, we are committed to delivering life-changing therapy to patients in need. The learnings from this study are important for the future of the Celldex pipeline across not only Barzolvolimab, but also CDX-622 and additional candidates in development.

The new data presented today continue to build Barzolvolimab's highly differentiated profile. While expected, it was reassuring to see that the loading dose combined with 4-week dosing demonstrated a favorable safety profile consistent with our prior studies and drove rapid declines in tryptase, which positions us well for our ongoing Phase III studies. In closing, Barzolvolimab has significant potential to become a transformational medicine for patients, and we are focused on driving mast cell category creation and delivering on Barzolvolimab's promise executing on ongoing trials and continuing to explore diseases of high unmet need where Barzolvolimab could play a role.

We look forward to sharing additional important information about Barzolvolimab in the coming months. We expect we will be in a position to report data in both the EMBARK CSU Phase III studies in the September, October time frame. As previously shared, we anticipate a readout of the Phase II data in AD late fourth quarter. And in addition, we look forward to sharing more about our broad life cycle development plans for Barzol later this year as well.

We appreciate your support and look forward to answering your questions tonight. As a reminder, these are top line results, and we are still reviewing the data. We will do our best to answer your questions, but may need to follow up at some point. Operator?

[Operator Instructions] Our first question comes from the line of Thomas Smith of Leerink Partners.

A couple, if I could. Just first on safety. I was wondering if you could provide a little more color on the clinical course for the aseptic meningitis case. Was there any neutropenia observed with this patient? Were there any other confounding factors? It sounds like the patient made a complete recovery, which is good. But any other findings you can add from the data monitoring committee review for this patient?

Sure, Tom. Diane?

Yes. So as I said, we don't agree with the investigator on the diagnosis of the causality. As I described, the patient did not have any symptoms consistent with that diagnosis. They did have an extensive workup as I outlined in the description and ruled out many different other causes.

We think that the clinical picture of the chest pain, which really went on for weeks and as well as the modest increased cells in the CSF really indicate some sort of neuro-inflammatory process, most likely due to a virus and they did not have any neutropenia. So the patient had absolutely no neutropenia through that.

Got it. That's helpful. And as a follow-up, can you just comment directly, were there any hypersensitivity or anaphylaxis events observed in this study? And then just maybe as a last question, could you just remind us from the Phase III CSU program, the timing and outcome of your latest Data Safety Monitoring Board committee and any potential read-throughs from this PN study to the CSU program?

So in terms of hypersensitivity, there were no cases of anaphylaxis in this study. There were 2 patients who discontinued treatment for urticaria. One was grade 3, one was grade 2. They responded to medications. In terms of the Phase III CSU, we're having regular meetings with the Data Safety Monitoring Committee. There's nothing particularly there. We do not believe that there is a read-through from these results today to do that those studies and those studies are really supported by very robust Phase II studies, both in CSU and in CIndU.

And we -- I would say from the standpoint of this study, so we have no concerns about efficacy, we feel, if anything, that this study, the safety profile really looked great even with using the higher dose. And we feel that, that reads through well to all of our indications.

Our next question comes from the line of Yaron Werber of TD Cowen.

I also had a question on -- in terms of some of the read-throughs maybe to atopic dermatitis, I know obviously, each condition is very different from the other, but maybe just remind us the biological support for running the AD study.

And then secondly, just on the CSU study, can you give us maybe a little bit of a sense on the DSMB side, kind of like what are they looking for in terms of -- we get a lot of questions as to what are elements that the DSMB is looking for that would drive potentially changing the study in any way? I know you obviously enrolled extremely quickly and 6 months ahead of schedule.

In terms of the DMC, there's really nothing particular. They have a charter. They review all the safety in an unblinded fashion on an ongoing basis and advise us on things that we need to do with the study, but there is nothing particular.

And we also have the adjudication committee. So all that's in place, Yaron, and it's been pretty consistent since we started the program in Phase I and nothing's changed.

Your first question, Yaron, regarding the read-through to atopic dermatitis and our rationale there. Certainly, both indications share some of the components of the pruritic disease and that was the basis for some of our rationale to move into atopic dermatitis after we had the Phase Ib data in PN.

However, there are different patient populations. Mast cells are known to contribute to other parts of the inflammatory process in atopic dermatitis. And we certainly plan on completing the atopic dermatitis study and look forward to the readout and the learnings from that study as we do appreciate that it's a different indication despite that they do share components of the role of mast cells and driving the pruritic itch part.

Yaron, do you have another question?

Our next question comes from the line of Iris Gao of Guggenheim.

My would also be on safety. I wonder if you can give more color on the frequency of neutropenia and skin hypopigmentation from this study and specifically in the 150-milligram group and also how soon was onset and stuff like that?

So as I said, we're very pleased with the safety data in this study. We had a low incidence of neutropenia, so it was below the 10% threshold that we are showing in the table. All the neutropenia were grade 1 and grade 2. There was no association with infection, and there was one discontinuation for neutropenia, which was grade 2.

As far as the hypopigmentation, there were 2 cases, 1 on placebo and 1 on drug.

Is any more color on like the onset of the skin hypopigmentation like we know how long it took for them to show up?

The skin hypopigmentation occurred for Barzolvolimab patient occurred at about the 6-month time point.

Our next question comes from the line of Kristen Kluska of Cantor.

First, I wanted to ask if any of the patients presented with comorbidities where you were able -- in a non-direct measurement way, able to see any effects? And then second, recognizing you're still digesting this data, I'm wondering if you're thinking about any thesis where this could be a potential candidate to further look at with a bi-specific in the future, especially considering there is a type 2 inflammation component to PN.

So I can answer. We're going to look at questions like comorbidities and do we have any anecdotal evidence in the study as we do all our programs. It's a little difficult because in the inclusion/exclusion criteria, you tend to want people that are fairly well controlled for their other comorbidities, but we will look. And I will let Tibor answer the question about bi-specifics.

Sure. Certainly, we look at all the learnings that we get from our studies with Barzolvolimab as helping us understand the role of mast cells and how that affects our pipeline development. So Kristen, we obviously consider the option, the possibilities of bi-specifics in the future, and that's something that as we think through this data deeper once we have all of that data in-house, we will look into very carefully.

Yes. And Kristen, we're also looking at biopsies that we've taken on study. We'll be analyzing those and comparing them to the Phase Ib biopsies since that was IV and this was subcu to see what we can learn from that analysis as well. So there's a lot of stuff we still need to do. I mean, we just got these data in a few days ago. But certainly, as we learn more, we'll communicate that out to everybody.

Our next question comes from the line of Sam Slutsky of LifeSci Capital.

This is Oliver McCammon on for Sam Slutsky. So first one for me is just as you think about mast cell biology post the urticaria PN and EoE randomized readouts, how are you thinking about indication expansion going forward and generally, the speed of the indication expansion for Barzolvolimab and CDX-622? And then I have one follow-up as well.

Yes. So we'll discuss more about where we're going in 2027 with Barzol later on this year. There are several indications that we're looking at, and we would imagine starting those studies up sometime in the first half of '26 or early second half of '26. Certainly, as we go through our criteria, it hasn't changed. We look at unmet need. We look at epidemiology. We look at the markets. We look at the ability to do studies and the probabilities of that.

So that hasn't changed. But I think as we look through and as we learn more, we'll have more information to share with you. But I think that we go through a pretty rigorous process. And certainly, also, we're trying to learn. We know mast cells are implicated, but what we're learning is that, especially in EoE and then now PN on the subcu formulations that does not meet our hurdle rates and it certainly doesn't have a big impact. So we're looking to learn, and we're looking to go back and take those learnings and move forward into new indications. So we'll update you on where we're going later on this year on that.

Got it. And then curious on why the aseptic meningitis patient received the lumbar puncture. Basically trying to get a sense of maybe whether/why they were worked up for this.

So as I said, the workup was -- went on over many weeks. There were several hospitalizations for workup. And they really had tests to rule out every possible cardiac, pulmonary and gastrointestinal disease. The patient did -- in addition to the chest pain, the patient complained of some weakness and had some decreased reflexes. And so they -- after doing all these other tests, they said, we should look at possible neurologic causes, and that was what caused them to do the lumbar puncture as part of a big neurologic workup.

Our next question comes from the line of Derek Archila of Wells Fargo.

This is Simone on for Derek. Just one from us today. So how should we think about the relevance of serum tryptase as a biomarker moving forward? And are you able to share the magnitude of tryptase reduction achieved and whether maximal mast cell depletion was maintained through week 12?

Sure. I'll take that question. So we believe serum tryptase has been a phenomenal biomarker to correlate with the clinical benefits of Barzol throughout the program and has correlated very well with what we've seen in terms of tissue depletion of mast cells. So currently, we -- this does not change our view on tryptase. While we haven't given the exact numbers, we certainly see profound depletion with the majority of patients getting below detectable levels, which are maintained throughout the treatment period.

So very, very profound impact on serum tryptase levels, which we believe converts to very good depletion of tissue mast cells. As Anthony mentioned, we do have some biopsies from the lesions of these patients, and we hope to gain some greater insight what's happening in the tissues, and we'll certainly report that when we have those data.

Do you have a time line on when you'll have that data or like any possible upcoming medical meetings?

No, we're still going through everything. As soon as we get it, we'll share.

Our next question comes from the line of Judah Frommer of Morgan Stanley.

I'm just curious if you have any updated thoughts. I know it's early, but just on drivers of the non-histaminergic itch here, I think beyond the well-validated cytokines from Dupi and Nemo. And then just specifically, any thoughts on MRGPRX2 ligands and the role they might play given the update here?

Tibor, you want to take a shot at that?

Yes. I don't think we have thought about this quite a bit. We -- as Anthony mentioned, we received these data, which were surprising to us just a couple of days ago. We're still grappling with the differences between our Phase Ib output and this study, which certainly raises questions about the role of mast cells in this indication. So yes, it's not something we've really thought about to address your question about what other mechanisms can be at play and what the role of X2-mediated activation of mast cells might be. perhaps after we do additional analysis.

Yes. So Jud, let us do the analysis on a bunch of stuff. And as we learn more, we'll be more than happy to share. We think this is important for the science going forward and for patients and anything that we can learn and share, we'll do so.

Our next question comes from the line of Alex Thompson of Stifel.

This is Patrick on for Alex. One quick question on the Phase III CSU top line, I guess, what exactly will be included? Are we only expecting to get the week 12 primary outcome? Or will we get that full 24-week data set?

You'll get 24-week randomized safety data with a 12-week primary endpoint. And again, it will be top line, and we will save the full data set for a medical meeting.

Our next question comes from the line of Andy Chen of Wolfe Research.

This is Jason taking in for Andy. I just wanted to ask about drug exposure compared between Phase I and Phase II since Phase I with IV. So we just wanted to ask in terms of the dosage for SC in the Phase II, did that change? Or was there anything accounted for when you guys went into dosages for Phase II?

Tibor?

Well, certainly, subcu delivery is going to give different kinetics of exposure than intravenous administration. And while we get very good sustained exposure with our subcu regimens, you don't get that rapid high concentration exposure. Whether or not this could have contributed to the differences between our outcomes in the Phase Ib or Phase II is unknown.

It's not something we can rule out at this time. Perhaps we'll learn a little bit more from the biopsy samples. But overall, as I've mentioned before, we had very good tryptase reductions. We believe we have very strong mast cell depletion in the tissues. And our conclusion currently is that mast cells are not a driver in this disease based on the data we have.

Our next question comes from the line of Richard Law of Goldman Sachs.

This is [indiscernible] on for Rich. Could you share any thoughts as to why based on the encouraging data that we saw and the alternative lack of effect that we saw in Phase II, could the formulation change from intravenous to subcu have had any effect? And could it have any read through ongoing trials using the subcutaneous formulation?

You were coming in and out. Can you -- I'm sorry to make you repeat the question. Can you repeat it?

Sorry about that. No problem at all. Yes, I was asking if you could share any thoughts as to why based on the encouraging things on the data with the IV formulation and then the alternative lack of effect to subcu, could that change in the formulation has had any effect and could have any read through to other trials using the subcutaneous.

So the only change in formulation is really the concentration of the drug. So I don't think formulation per se was an effect. The route of administration, as we've discussed, is something that we're still trying to understand. There certainly is precedent for some treatments where intravenous induction is optimal for effect. And so whether that's a situation here or not, we don't know.

But we believe that with our subcutaneous formulation, we are impacting the mast cells the way we expect to and certainly has led to dramatic effects in our clinical outcomes in a number of other indications. So we still have some work to do with the biopsy samples here to demonstrate that, but we're quite pleased with our subcu formulation.

Okay. Got it. And just one follow-up, if I may. Is there any read-through in your view from these studies as well as EoE, PN to CDX-622? And could that drug work when [indiscernible] indication?

So we're, again, still learning from these studies. If we don't believe that mast cells are a key driver, then it's definitely not a high priority indication where 622 is also working at least through the mast cell depletion as part of its mechanism of action. So we'd be focused where there is clearly a role for mast cells, but other -- that also includes other drivers in the case of 622, that being TSLP. So yes, if we are finding out with Barzol that mast cells are not playing a critical role, that diminishes the potential for 622 in those same indication.

I would now like to turn the conference back to Anthony Marucci for closing remarks. Sir?

Thank you. And everyone, thank you for joining us tonight. We know this was short notice, and we appreciate all the time and the questions tonight. We look forward to coming back in a couple of months, September, October time frame to discuss our CSU readout. And in the meantime, if there are any questions moving forward, don't hesitate to give us a call. Have a great night.

This concludes today's conference call. Thank you for participating. You may now disconnect.

Good afternoon, everyone. Thanks for joining us here on day 2 of the Leerink Partners Global Healthcare Conference. My name is Tom Smith. I'm one of the senior biotech analysts here at Leerink. And it's my pleasure to welcome our next company to the stage, Celldex Therapeutics and represented today by President and CEO, Anthony Marucci; CSO, Tibor Keler; and CMO, Diane Young. Thank you all for joining us. Looking forward to the discussion.

Yes. Great to see you again, Tom. Always good to talk to you.

Likewise. And to set a little bit of the state. 2025, great year of execution, some very good data points. I think for investors, clearly, a lot of focus around the Phase III CSU readout that we're now expecting in Q4 of this year. Study enrolled rapidly, way ahead of schedule, overenrolled. It seems like there is -- we interpret that as evidence of clinician demand for better urticaria therapeutics, also patient demand for folks that are -- as a population we think has been pretty underserved historically. Anthony, maybe you could kind of kick us off and level set us highlights from 2025 and then what else we have to look forward to here in 2026?

Yes. So 2025 was, as you said, a year of execution. Finished up our CIndU studies and our CSU studies. So off of CSU, we finished our 52-week therapeutic study where we dosed patients out to 52 weeks, and then follow that on with a 28-week follow-up period for those patients, and we presented our 76-week data. And in both of those studies, the data was unprecedented, right? So at 52 weeks, we had up to a 71% complete response rate, followed those patients out for another 28 weeks. And at 76 weeks with patients off drug, 41% of those patients still had a complete response.

The same thing for the CIndU study. We did our 12- and 20-week studies, finished them up in 2025. We presented the 12-week data. Again, really excellent data there. And then starting future studies. So we initiated the Phase III study in SD and ColdU at the end of December, and that led us into 2026.

So you pointed out that we started the year by announcing the Phase III CSU studies accrued 6 months ahead of schedule. They were the largest studies ever conducted in CSU patients that were antihistamine refractory and biologically refractory patients. We accrued 1,939 patients was 109 patients above the level that we set. We were in 500 sites. We're in 43 different countries. So great execution by our ops team, great kudos to our partnerships with our CRO and Diane's clinical science team, but it was a collective effort. Tibor and the CMC team made sure that drug was available to all these places on top of managing the CDMOs to get through Phase III and commercial development for manufacturing.

So a big lift, as you can imagine, for a company our size, but certainly one that we relished in the fact that we could do it. We did it in a speedy time limit. And again, there was an unmet need here to around the excitement. Interestingly, we had a good mix of allergists and dermatologists on the study. In the U.S., where we accrued 26% of the study in the U.S., 53% of those patients were put on by derms, something that surprised many investors thinking that it would be more just allergists. So again, we're just very, very happy and satisfied by what we've seen so far, and we look forward to flip the card in the fourth quarter.

That's great. And yes, I want to double-click on that data point because I know you guys very thoughtfully wanted to make sure there was a representative derm presence in this study to be able to drive potentially like the broadest uptake of the product possible. I would be curious if we have feedback, I guess, from the dermatology community over what drove them to? I'm also surprised, it sounds like you were surprised as well that the majority, but the majority of patients in the U.S. are coming from dermatology practices. We've historically thought of this as more of like an allergist-driven.

Yes. We just thought because of the severity of the patient population that we saw in the Phase II study, where 70% of the patients were considered very severe that you wouldn't see the uptake by the derms in Phase III, but we were very happy to see it.

Yes. Remind us -- one of the other design elements we always liked about the study is you're enrolling the biologic experienced patients. Do you have a sense for kind of how that card has flipped over, like a proportion or a certain proportion that we were targeting?

So the only thing we know at this point is 75% of the study was antihistamine refractory and the other 25% was biologically experienced or refractory. That's what we know at this point.

Great. Okay. Excellent. I want to talk about the data that you just presented at Quad AI. And look, we've always thought of this as your high efficacy option, unprecedented complete response rates that you alluded to in your opening comments, Anthony. I thought what was really intriguing out of the Quad AI data was the durability of effect. I felt like was on full showcase. But maybe you could just walk through sort of the highlights of that data set in CSU, and then we'll come back and maybe talk about the commercial implications of what you're seeing clinically.

Yes. So the -- so what we showed was a subset of the patients from the CSU Phase II study, and we were really focusing on that durability of response off treatment. So we had the patients who had well-controlled disease at 52 weeks and then saw what happened to them as they went out to 76 weeks. And again, very, very high rate of maintaining complete response. Those that did relapse, relapsed with mild disease. And you can -- there's -- it's a beautiful figure, kind of a heat map of response. It's really hard to describe.

But -- and we were able to show this. We looked at the PK, and we showed that we had this complete response that was persistent despite the fact that barzol levels were below the level where you would be expecting to have significant KIT suppression. And also, we did see tryptase coming back to normal levels. So really interesting. And Quad AI also picked that up as a poster to highlight in their press release, which was really nice.

So this was looking at patients who achieved response, basically like well-controlled disease, about half of them were complete responders, like 7 months removed from treatment. Like we think of that as relatively unprecedented. But I want to talk about kind of the clinical implications of this, like what -- do we think that this is truly disease-modifying?

I think it raised -- what our experts have said to us is it certainly raises the question of disease modification. It's not -- there's not a standard definition in this disease. But we certainly have a much longer response than can be explained by pharmacokinetics alone. And it is longer than you would expect -- there is spontaneous remission, but it's a much higher rate than you would expect from that. So there's something about it that is causing this prolonged response.

And what's the potential like biologic rationale for that? Is it that you are totally depleting, wiping out mast cells and the mast cells that repopulate are a different phenotype lineage?

Yes. So certainly, we think the mechanism of action is what's at play here, the ability of Barzol to really take out the effector cell in this disease and keep it out of the picture for a long period of time. So when these slowly come back and do come back, we're not seeing the same level of disease in those patients. We followed them out to 76 weeks. It's certainly likely that eventually more patients would see their disease return. And that's still a really unprecedented length of time for controlling disease without treatment.

Yes, fascinating. And then -- sorry.

Yes. And again, it speaks to the severity of the disease. What our health experts are telling us that the longer you have had the disease, right, if you're going out 4, 5, 6 years, the less likely you are to have any kind of spontaneous remission. 7 years on the mean of duration of disease. So these weren't patients that were going to remarkably remit quickly and to see that kind of response post the data and post submission, it was just remarkable to us. So we think it has a lot of implications going forward.

Could you talk about the potential commercial implications of the drug with that profile? So I suppose one aspect is just like unprecedented efficacy also could introduce potential either intermittent dosing or a curative like effect that how does one potentially price for something like that?

Well, that's a discussion we have to have when we talk to the payers when we get there, and we got plenty of consultants to help us out with that. But I think as we look through the data sets, there are a couple of things that jumped out at us. As Diane said, we did have a more severe population. And originally, we were just looking at the UAS7 scores. But what we also saw is that we had a high rate of patients with severe angioedema on the study. So when you put those 2 numbers together, it turned out to be a good 1/3 of the study, 36% of our Phase II, whose patients had both severe UAS7, CSU and they had a mean score of 53 on their angioedema score.

So for anybody who understands angioedema, a score of 19 is considered severe. And the mean on our Phase II study was 53. And with that, we saw a remarkable control over UAS7, which is the angioedema score. And we also saw that improvement of life -- quality of life as well as the complete responses. So when you take all 3 of those pieces of efficacy into consideration, there is a path for both frontline inclusion for those patients that have severe angioedema and severe CSU. And then the other entry point, which would be second-line advanced label post a Dupi or post a Xolair or Remi going forward. So those are the 2 areas where we see an entry point and something that I don't think a lot of investors were paying attention to.

That's very interesting. I want to talk about the EMBARQ CSU study. And you've implemented a loading dose there. Obviously, you didn't have that in the Phase II experience. Talk about potential impact on both efficacy and safety with the loading dose?

Yes. So as you said, we're using the same doses we had in the Phase II, but we have added a loading dose to each one. So a 300-milligram loading dose to the 150 Q4-week arm and a 450-milligram loading dose to the 300 milligram every 8-week. And we really did this on the basis of looking at the data from the study and modeling. And it looked like with the subcutaneous dosing in the study that we get a little bit faster response initially with the 300-milligram dose, but we also see that over the 8-week period of time it starts to come back a bit.

So with a loading dose, we can sort of smooth that out and hopefully get more rapid efficacy upfront. And we don't think it's -- so we think it's going to produce better efficacy, particularly early, and we don't think it's going to cause any issues with the safety profile at all. We have looked at that level of loading dose in our other Phase II studies going on. And we have certainly looked at higher exposures than that when we were looking at intravenous dosing. And we don't really see a difference in terms of the safety profile.

That makes sense. Let's talk about expectations for the Phase III and I guess, how we're framing those. The Phase II results is quite compelling. Obviously, a replication of that would be the...

Mind-blowing.

Yes, the best pivotal results we've seen in urticaria. The agents that are currently approved and that we have late-stage data for all look relatively similar kind of in the Xolair range of efficacy. Just sort of help us frame like how you think about good results? Is it just something kind of north of what we've seen from the Xolair? Is there a certain threshold that you're looking for?

I think our expectation is that we would have data similar to our Phase II data. I mean that's what we're hoping for, especially when you add in the loading dose, which, again, we're just trying to get a better effect early on. At the end of the day, whether you're getting the 150 or the 300, you're getting similar doses anyway, but it's just a matter of can you get those responses faster. So that's our expectation. But at the same time, being a finance person, you're always modeling in improvement in the placebo rate, a decrease in your drug rate. And at the same time, we powered the study 90% to show a 10-point improvement. I mean that's the hurdle.

And we think the study is very much well overpowered. And then on top of that, we also powered at 90% to show a 10-point improvement in the refractory population. So I think if we can get anywhere near what we had in Phase II, it's an absolute slam.

Yes. And just to build on that, but on the safety tolerability side, similarly, replication of Phase II, we would be very comfortable with that. Is there anything particularly that we're looking for or anything that we're kind of managing around?

Diane go ahead.

No, I would say we're looking to see a similar profile to what we saw in Phase II.

Yes. I mean we've already had 600 to 700 patients already in our various studies. So I think we're very comfortable with the safety profile. So if we can match up the safety profile in the Phase III, that would be remarkable. Because remember, the neutropenia was all transient. The hair lightning and the hypopigmentation were all grade 1, very, very mild, and they do reverse. So that's our expectations going forward.

Right. And just remind us the long-term experience there. I think it was about 3/4 of patients stayed on drug and of those like 3/4 of patients complete responders. Is that right?

In terms of...

In terms of long-term CSU over the course of the year.

Yes.

Yes, okay. That's great. Let's talk about the market opportunity. It's fairly dynamic times. We have Rhapsido that was approved, remibrutinib seems to be launching well. I guess any early market feedback that you're hearing on that launch? And how does that launch shape the way you're thinking about kind of where barzo fits in?

Yes. So again, like I said, where I think we fit in are 2 entry points, right? So they're both areas where we think the data is superior, and that's in these severe angioedema patients and severe CSU. The other entry point is you don't do well or you're not completely controlled on Xolair or Remi or Dupi. We would be the drug of choice in second-line advanced therapeutics, that's the way we look at it. So we feel that we have a clear space to operate, right? We're not competing with them.

What we're hearing about the Rhapsido launch is that it's going well, that doctors seem to like it. And we expect that it seems very Xolair like in its efficacy, but it's an oral. So you got to take it twice a day every day. And if you miss doses here and there, you tend to hide pretty immediately. So -- and not unexpected. But evidently, we think that's gone well. And I think longer term, that's good for us, right? It's been an underserved population. We know that there are plenty of CSU patients out there. We have so many companies targeting CSU as an indication with their drugs. There have been 28 companies that have targeted CSU as an indication for their drugs. And it's Sanofi and it's Novartis and Roche, Novartis with Xolair and hopefully now us that have succeeded. Everybody else has not done well. And that includes companies that have $1 billion drugs elsewhere.

I want to talk about inducible urinaria where we've launched the Phase III. And other one we saw data at Quad AI from the inducible urticaria experience. You actually had a late-breaking poster at Quad AI. So maybe just kind of hit the highlights on that data set. And then for the Phase III CIndU experience, like are there tangible learnings we can take away from the urticaria operational execution enrollment aspect that we can apply to CIndU?

Yes. So the data that we showed at Quad AI, the late-breaking poster was retreatment data. So in the CIndU Phase II, they received 20-week placebo-controlled period. And then when they were in the follow-up, if they recurred in terms of symptoms, they could be retreated. And what we showed in that poster was that as we really expected, when you retreat, you get the same response as you did initially. So there was no diminution in the response and the safety profile was very similar. So we expected that, but it was just -- it was nice to see that. The other data that we presented was 20-week placebo-controlled data, just showing improved quality of life and urticaria control.

And in terms of what we've learned from the CSU study, I think we've learned a lot. We're actually going back to many of the sites that we used. It's a smaller study, so we don't need so many sites, but we're using the same CRO. We're going back to the site -- the same sites. I've gone to the investigator meetings and the investigators are all very well trained in barzolvolimab. And so it's been -- it's really -- this is a very easy study to get started.

Can you talk about the translatability of -- I mean, unprecedented efficacy, I would argue, in both CSU and CIndU, like other considerations now as we move into large Phase III cold urticaria and SD studies. The endpoints, I think, specifically in cold urticaria have been little tricky. But just maybe walk us through how you've designed and how you kind of like optimized for success on -- in those settings?

Yes. So we are using the same endpoints to -- as we did in Phase II in terms of the primary endpoint being complete response by provocation test. That's what we used in Phase II. That's -- we've gotten alignment on that. We are also incorporating into some of our -- into our secondary endpoints, some patient-reported outcome data, particularly looking at itch as well, which is something we learned from our Phase II study. But it's -- and I would say that from -- we learned a lot from the Phase II about how to use those provocation tests, how to instruct the sites and things like that, that are useful in terms of the Phase III.

I want to switch gears from urticaria to -- we have a couple of other data sets coming this year. We'll start with prurigo nodularis. And it sounds like we may get that Phase II proof-of-concept study first potentially. You have Phase Ib data. really nice signal that was with the IV form of the drug. I guess 2 things. Just like remind us -- level set us on the rationale for depleting mast cells in PN and how that translates to clinical effect. And then when you think about translating the Phase Ib to this Phase II study, like remind us of the differences besides just we're using the subcu now?

Yes. So the rationale is really that there has to do with the mechanism of itch. And there's -- it's actually a growing area of research about the relationship between mast cells and sensory neurons and the involvement in diseases with itch. And prurigo nodularis is such a disease. We actually started our research because we saw a case of prurigo nodularis in our CIndU, our original Phase Ib CIndU study, and it completely responded. And that led us to do our Phase Ib in prurigo nodularis, which was a study that had single doses of barzolvolimab at 3 milligrams per kilogram and 1.5 milligrams per kilogram and placebo, and we treated moderate to severe prurigo nodularis patients. And particularly at the 3 milligram per kilogram IV dose, single dose, we saw a 57% reduction or 57% of patients had at least a 4-point reduction in itch at the 8-week time period. And we also saw healing of lesions, particularly again in the 3-milligram per kilogram group.

The other thing in that study was we looked at tryptase, and we did see a difference in that indication between the 3 milligrams per kilogram and the 1.5 milligrams per kilogram in terms of level of tryptase suppression, which was different than what we had seen in urticaria. So in setting up the Phase II, we went to subcutaneous dosing, and we are looking at higher dose of barzvolimab than we looked at in urticaria. So our highest dose, we have 2 doses. One is 450-milligram loading dose with 300 milligrams every 4 weeks. And then we have 450-milligram loading dose with 150 milligrams every 4 weeks. And it's 2 doses versus placebo. We've completed enrollment, and we're going to have the data this summer.

Yes. So just to level set when data is coming out. So the PN data will come out first in the summer followed by the CSU Phase III studies sometime in the fourth quarter and then the AD data set from Phase II towards the end of the year. And that will be the order of when we're putting out data.

That's great. PN, just from a market opportunity perspective, I mean this is one I feel like investors, it's a smaller opportunity. The patient numbers are lighter than in many other dermatologic conditions. But we do have Nemluvio that seems to be doing pretty well. Dupixent, it seems like also -- how do you think about, I guess, the potential commercial opportunity in PN?

Yes. Once again, I think it is a smaller indication. I would equate it to CIndU, which is around 1/3 of the CSU population. But again, I think it's also underserved and underdiagnosed. So I think as the Nemluvio's are out there, as the Dupi's are out there, as we hopefully will get out there in PN, it will be easier to find the patients. It will be easier to treat the patients. And again, I think the market is bigger than what we're all thinking, right? There's very few markets that I've ever looked at that turned out to be smaller than we thought of, especially as we did more work. So I think PN is another one of those disease indications that's underdiagnosed.

Yes. And last question on PN. How are you framing expectations for this Phase II Study?

So again, we'd love to mimic what we had in Phase I. We're always looking to be at least as good as the current standard of care. And again, both Nemluvio and Dupi got approved pretty much around the same time. And -- but we think that if we have an effect on the NRS scores, which is the itch, and we also have an effect on the lesions in a bigger way, I think that's your differentiator.

Yes. let's talk briefly about atopic dermatitis and comes last this year. But a little bit different, I think, biologic rationale there. We don't know necessarily that AD is a mast cell-driven condition. But I guess, like how are you guys thinking about like what's level of excitement around the AD readout, I guess, level of conviction that we will see a signal there? And what does a good signal look like in this Phase II study?

Yes. So I think AD was kind of an extension of the PN in terms of itch is still one of the predominant symptoms of AD. There do seem to be neuro immune mechanisms involved in the itch. So -- and there's other roles that are hypothesized for mast cells in terms of the complex pathophysiology of AD. So I think we would say that with PN, we had -- with the PN Phase II, we had clinical data. We have responses in our hands in AD. It's -- we don't have that level of certainty with that much data, but we think it's a reasonable hypothesis to test.

And again, we would be -- we say we would like to be as good or better than what exists. I think from a commercial standpoint, we would see this drug fitting in after the standard of care with Dupixent, but before a JAK inhibitor. So that's the kind of position.

Are we enrolling biologic experienced patients?

We're enrolling -- it's an all-comer study. So we're enrolling everybody.

Excellent. Okay. In the last minute, we're not going to do this justice, but I want to talk about CDX-622. We've generated some healthy volunteer data. We put it in a proof of mechanism study in asthma. Just talk about biologic rationale for going there with TSLP stem cell factor. And what patients are we enrolling in this proof of mechanism? And when could we see data from this?

So yes, so we're in Phase I, both in healthy volunteers as well as in this proof of mechanism study. The concept with these more moderate asthma patients is to get PD data around both the impact of inhibiting TSLP as well as inhibiting mast cells. And because of the work that's been done with approved TSLP inhibitors like TEZSPIRE, where there's a really clear biomarker pattern that we would expect to see. So this is more validation work on this molecule for proof of concept. We think asthma is certainly an indication of interest as well as other pulmonary indications. It's a small open-label study. We're not directing in terms of exactly when we would be presenting data. We are presenting data in Q3 on the healthy volunteer study, which will include the multiple ascending dose as well as subcutaneous dosing.

Awesome. All right. We'll stay tuned on that front. Big year ahead. Looking forward to all of the results this year, but especially the Phase III CSA data.

Yes. As we all are.

And thank you, Celldex team for joining us.

Thank you.

Thank you.

Okay. Well, welcome once again, everybody, to the 46th Annual TD Cowen Healthcare Conference. I'm Yaron Werber, biotech analyst here at TD Cowen, and it's a great pleasure to moderate the next fireside chat with Celldex. With us today, Anthony Marucci, President, CEO and Co-Founder; Tibor Keler, EVP, Co-Founder and CSO; and Diane Young, Senior Vice President and Chief Medical Officer. So team, thanks for joining. We appreciate it.

Thank you. Appreciate you having us.

Lots going on, lots of big announcements on finishing both enrollments in the CSU, the EMBARQ program and starting the Phase III CIndU study as well. So it's going to be an action-packed year for this year, plus prurigo nodularis data and AD data. So lots really going on.And 622 data, and we only have 28 minutes just to orient us. So maybe the faster than enrollment than expected enrollment for EMBARQ despite competition, what does that tell you? And kind of what are you seeing? Is the enrollment more U.S.-centric? Is it really global in nature?

No, it's global in nature. And certainly, we just think that there's an excitement around the drug. There's an excitement around the PIs that were on the study. And certainly, you had Remi getting approved this year in '25. You also had Dupi getting approved and then the face of that to accrue a study 6 months prior to your guidance. We over accrued the study because we had patients in screening when we announced that we were going to close. So it's just a tremendous amount of enthusiasm, we believe, for the drug, for how it went and for the future of it.

And then can you just remind us what you said on powering for the studies and your ability to then obviously combine them as well?

Yes. Well, so the studies are 90% powered to see a 10-point difference in the mean change from baseline in urticaria activity score 7 compared with placebo. But very importantly, it's powered to see that in -- both in the overall subset and in the overall group and then in the subset who are refractory to omalizumab. So the overall group is overpowered in the sense.

And what about the powering for that subgroup.

90% to see a 10-point difference, yes.

Excellent.

I mean a 10-point difference is very doable. I mean it's massively overpowered given the data. And it's at 52 weeks.

12 weeks -- sorry, 12 weeks is the endpoint. Yes.

12 weeks, but the study is 52 weeks...

The study is 52 weeks. We have a placebo-controlled period for 24 weeks and -- but the primary endpoint is at 12 weeks.

And when you're looking at both subtypes, subgroups, the naive and the experience, are you expecting similar results in both based on the previous data?

Based on what we've seen previously in our other studies, it looks like there are similar kinds of responses in both groups. This is obviously a much larger data set, but we expect to see similar results.

With -- as you kind of think about what the bar is, what your sense is the bar maybe even in the Oma experience?

I mean we're looking for statistically significant benefit. Our rates are higher than anybody else's. We're looking -- we're hoping for the same thing.

Yes. So the interesting part coming out of the Phase II study, Yaron, was that our 76-week follow-up data, the complete response rate there was 41%, and that was higher than any of the competitor drugs while the patients were on treatment. So as you remember, at 12 weeks, it was upwards of 51% at 52 weeks. It was deepening in upwards of 71%. So we really appreciate the fact that this drug works very, very well, works very, very rapid. And the deepening of response is also something that we're truly glad about.

And I would just say for omalizumab refractory, there is nothing that's been approved or has demonstrated statistically significant efficacy in that population.

And what about -- can you just remind us what did Remi show in that population?

So Remi has not precisely looked at that population. They have done analyses where they've looked at omalizumab experience. They don't see a statistically significant difference that they've reported. They do see some -- it looks like they have some activity there, but they haven't -- it's not sized to look at that.

And what was the magnitude of the difference even not start saying?

They see kind of a difference similar to what they're seeing in their overall population.

Is the study powered to look at 2 different doses? You're doing 300 loading with 150 every 4 weeks and 450 loading and 300 every 8.

We didn't specifically power it to look at a difference in doses.

And so based on that, you decide which one dose or both to file?

Correct. Correct. And often, FDA will approve several -- a couple of doses because it's good to have options.

You noted the 76-week data. And at that point, patients were off therapy for about even as long as 27 months, right? And the mast cells repopulate by 28 by 2, 3 months completely?

So yes, based on our -- the tryptase levels coming back throughout this 7-month period, we know that they're at normal tryptase levels, which indicate that patients' mast cells are back to the same level as you would see in healthy patients or healthy individuals.

And so what confers that activity in your view, the durable activity?

Well, I think you have this profound impact on the effector cell that's driving the disease. And in these patients where you've really shut this down for a full year, I think there's a profound effect in terms of the timing that it requires for the disease. I mean, we do expect that in the majority of patients, the disease is likely to come back, but it comes back very slowly because you are repopulating these mast cells slowly. They may not be as sensitive to the triggers as they were when the disease was flaring for them initially. So we're still learning about exactly what's going on, but extremely pleased with this unprecedented activity.

With respect to what you might be able to include in section -- clinical Section 14 in the label with this long-term data, does it have any translatability? Or is it going to be mostly coming from the Phase III?

I mean, probably most of the data in the label will be from the Phase III. That's the precedent, and that's what we have to discuss with FDA, obviously.

We clearly have very strong publications that will outline this activity. I think that will help support it.

Support and that's something the [ MSLs ] and...

Absolutely...

But the thought is not to have a treatment-free period necessarily.

I don't know. In our initial label, I don't -- that will not be...

No, we want to give the docs that optionality.

Would you consider doing a Phase IV study with like, let's say, Q12-week dosing where you get to effect in 24 weeks, you go less durable?

You're asking me to spend more money Yaron. Yes. There are certain things that we would want to do in Phase IV. That's certainly one of the options that we would have. I'm sure Diane and her team can come up with other things that they want to look at, but I'm sure that's one of them.

What else would come to mind?

I think there's going to be all sorts of questions. And just to mention, we consider Phase IV type studies. There's also -- in this field, once something gets approved, the treating physicians themselves often use the drug in new ways and try to give it so that the patients will have the best experience.

Yes. Right, longer dosing period...

Longer dosing, double the dose, more frequent, less frequent.

Intermittent. Yes, those types of things.

Okay. Any questions from the audience? If anybody has any questions at any point, just go ahead and raise your hand and happy to take it.

Just a reminder. Looking at Phase II data that we are seeing and the things [indiscernible] inclusion/exclusion criteria? Did the patient population -- was the patient population pretty fast or pretty similar or not?

Patient population, exclusion -- inclusion, exclusion was the same. The only thing we changed is that we did a loading dose.

Correct. And it's obviously a broader geographic distribution, but we kept the criteria the same.

Just because you enrolled so fast, we've seen other companies that enroll really quickly and then they kind of get off kilter on the actual patients that got into the trial.

Tried to keep it exactly the same.

Yes, same patient population.

Since we're pretty close to commercial -- since we're closer to commercial than we were to actual data, any thoughts on pricing? Like are we thinking Xolair as a comp? Or is -- how are we thinking of pricing now?

We're doing that work now. Certainly, we have a ways to go before we can declare what we think it is, but we certainly are looking at a premium to where Dupi, [indiscernible].

When -- in terms of some of the AEs and monitoring in the study for neutropenia, hair changes, it just standard when they come in and how frequently are patients coming in?

So in the study, patients are coming in on a monthly basis. And what was your initial question?

And then secondly, from -- once you're on the market, what are you anticipating in terms of monitoring? Is it just sort of baseline early on and then cadence of normal visits or anything particular comes to mind?

Yes. No. So we've been -- in terms of the question monitoring comes up most frequently with hematology. We've been very pleased with the consistency of the data across our study that we have neutropenia events. They're mostly mild. They reverse while the patients are on therapy, and we haven't seen any association with infections. So it doesn't seem like monitoring would be beneficial in that situation.

And in terms of surveillance overall for hypersensitivity, how is that done in the study?

That's just adverse event reporting. You capture adverse events when the patients come in to visit the physician, you ask them if anything has happened and they report it.

Okay. Any update on the sperm study in men?

It's ongoing. We expect the study to read out in time for our filing for the BLA. That's the requirement.

And so that's this year?

We haven't guided on the exact timing.

We've said by the time the BLA -- Yes.

How is that study done? It's healthy volunteer and it's a short-term study...

Yes, we're giving healthy men clinically relevant dose of barzolvolimab, following them, obviously, understanding their impact, not just on their sperm count, but on other aspects of their sexual life of their hormone levels and all that's going to be captured and reported in. And just to remind folks that this is a known impact based on KIT biology that systemic inhibition of KIT will impact the maturation of sperm. It's 100% reversible. We've demonstrated this in our prior preclinical studies and certainly expect to see the same with our studies in men.

In nonhuman primates, have you seen changes in hormone levels as well or just for [indiscernible]?

We actually did not do hormone level analysis in the preclinical study.

Okay. So as the market is getting more competitive, where do you think based on the data, barzol is going to get used? And is it slightly different initially, let's say, first year or 2 versus year 3 and 4?

Well, certainly, years 1 and 2 and 3 and 4 can be a little bit different. But we believe that there are 2 entry points for us coming into the market. The first entry point would be frontline -- first-line advanced therapy in those patients that have severe CSU and severe angioedema. And we look at that from our Phase II studies where we looked at both severe CSU numbers severe angioedema numbers. And the way we measured severe angioedema, as you know, Yaron, anything above a 19 is considered severe. We went and looked at the median numbers in our study and the median numbers were 53.

So we looked at both the UAS7 of greater than or equal to 28 plus an angioedema score of greater than or equal to 50 and 36% of the patients on that study had both. So if you want to look at it commercially and say, okay, I'm going to cut this number in half. We have a good entry point into that frontline therapy using those. And then the other entry point would be the drug of choice in second-line advanced therapy, right? So if you take Xolair or you take Dupi or you take Remi, once you go through those, whether you don't do well, whether you don't tolerate, whether you're not getting the control you're looking for, you drop down to barzol. So we think that, that is an excellent entry point on both.

We certainly believe now that with [indiscernible] and Dupi on the market, it's going to certainly grow that market significantly. It's been an underdiagnosed market forever. And I think the analogs that I would leave investors with is go look at the psoriasis and the rheumatoid arthritis markets, whereas more competitors came in, the diagnoses became quicker. And then long term, you think that those second-line advanced therapy indications, that population becomes larger than the front line. So we think that it's got an excellent opportunity here.

And just remind us the loading dose is an IV loading dose and...

Everything subcu.

Subcu in the office?

Yes.

And then from that point in the study, it was health care or a caregiver administration?

Yes...

No, all of it's in office administration in the study.

And then would it be outpatient in the real world? So patients can self-inject at that point?

They can self-inject. We're looking -- we're going to start -- go commercial with a prefilled syringe in office. And the goal is within the first year to have a self-injected, auto-injector.

In the first year. Okay. But the prefilled syringe, they could still take at home as well.

They could.

No. Well, we won't -- we won't have -- you have to have all the instructions for the patients and things like that. And that's -- it's some additional work that we have to do to...

Before -- if the auto-injector isn't available you can still inject it...

Yes, that's correct.

Okay. And the auto-injector is about a year behind or so?

We would say so. We're doing the work on that now.

Any questions from the audience?

Then maybe let's move to CIndU. So you presented the data at ACAI in '24, both in ColdU and SD. And now you're starting your Phase III, the EMBARQ-ColdU and SD study, 240 patients, 1:1 randomized. So here, you're doing a 450 loading dose and 150 Q4 weeks, right, against placebo. In the Phase III, sort of the 300 was a little bit better in ColdU and 150 was a little bit better in SD. Maybe help us understand why choose that one and not the higher dose?

Yes. So both doses were active in the Phase II study, as you mentioned, both of them were statistically significant in both forms of CIndU. When we came to design this study, because CIndU is a rare population than CSU, we wanted to just look at one dose to try and keep the study accrual times manageable. And we felt that 150, we had a lot of good data on. We do feel that the loading dose would augment the rapidity of the response at the beginning as we decided for CSU. So this is what we selected to go ahead with CIndU. I don't know -- did you have anything else?

No. I think this is a great compromise when you're doing a single-dose study. And I certainly expect that 150 monthly or 300 Q8 weeks is really a similar...

And you're using the higher loading dose here -- point, right, to get yourself a faster onset. The -- so Novartis recently assumed that the REM IND study showed stat significance against both and they're filing an IND. What -- how well diagnosed is CIndU relative to CSU? It's obviously about 15% of the overall market.

I think there's actually been less work done on CIndU and now that's starting to change. But I think CIndU faces all the same problems as CSU. I mean I think there are some patients where they might have a very clear association like if you have a ColdU and very severe reactions, that's probably easy to figure out. But some of these -- some of the other ones may be more challenging. So I think that CIndU is probably underrecognized, undertreated, et cetera, just like CSU.

Yes. And again, drugs coming on the market is only going to make that market more available to be diagnosed. And then certainly, if the drugs work, you'll see more people getting treated.

Yes. Maybe let's go back to CSU for a second and Dupi. How do you think Dupi is getting used just given the data? So the data on the oma experience wasn't good. So it really should be for Oma naive, but Oma is going biosimilar late this year.

I mean, I've heard that it's being used with comorbidities. So if you have AD and you have a concomitant CSU, it's being used there. But we don't have all the information that you probably would want.

We also hear that dermatologists may be trying it because they're so familiar with it. So that seems to be the other group.

Not a great drug, but easy drug to give or drug they're comfortable with. Okay. Let's move to the PN study. And maybe just remind us the trial design and what you said on timing? And then maybe we'll talk about the Phase Ib data.

Yes. So the PN Phase II randomized placebo-controlled trial, we're looking at 2 doses of barzolvolimab versus placebo. We have 24-week placebo-controlled period, 12-week primary endpoint. We're looking at patients with moderate to severe prurigo nodularis. The enrollment is completed. The planned number of patients was 120, and we had 140. So we're now in the process of cleaning the data and getting ready for data readout later this year.

So in the Phase Ib, this was 24 patients. It was only a single dose, right? Showed a clinically meaningful 4-point reduction in itch, 57% of patients on the lower dose and 43 -- actually, I'm sorry, at the higher dose and 43% at the 1.5 mg per kg lower dose achieved the endpoint at 8 weeks versus, I believe, 25% or so on placebo. There's also obviously good data on skin clearance and almost clear and clear versus essentially none on placebo. What's most important in PN? Is it skin clearance? Or is itch?

I think they're both important. It's -- I mean, PN is one of the most pruritic diseases that there is. And the itching actually -- the chronic itch contributes to the lesions getting a lot worse. But I think the lesions are also very disfiguring and very uncomfortable for patients. So I think what patients want is both. They want rapid relief of itch and they want clearing of the lesions.

And that's our differentiation. If we have an effect on both, and I think we've shown that we do, small patient population, but we'll see it in Phase II. If we have -- if we work on both ends, that's a win. .

And the 2 doses that you're using, is it the same 150 Q4 and 300 Q8?

No. In that study, we're -- our higher dose is 300 Q4, and then we're using 150 Q4. And the reason we went with a higher dose there was because in the Phase Ib, it looked like the 3 milligram per kilogram worked better and the tryptase suppression was more complete. And that was a little bit different than what we saw in our early studies with CSU. So we wanted to make sure we included a high enough dose to look at everything.

We want to make sure we don't underdose those 2.

And the loading dose is still 300 -- or is it 450 as well? It's 450. So everything -- because it's a much more -- right, it's a higher severity disease essentially where it needs higher suppression. And is it powered against placebo...

Yes, each arm versus placebo.

Each arm is about 45 patients or so.

It was -- well, it's -- we had 140 total patients, but we planned for 40.

Yes.

Okay. So it is powered against placebo.

Yes.

Is the next step a Phase III? And is the primary at 12 weeks? Or is the primary longer?

We're going to follow what the others have done, whatever if it's 12 weeks, we'll do 12, if it's 16, we'll do 16. But we're going to follow the path that's already been provided for us. So whatever that is, it's probably a 12- or 16-week endpoint.

Yes. But we'll certainly let the data guide us as to what our best features to differentiate might be and have endpoints related to that.

Okay. And so you mentioned the data is this summer.

Yes.

Yes. So then the next program is the Phase II atopic dermatitis, and I think the data for that is late this year, right?

Correct. Cadence will be PN, the CSU Phase III and then AD later on.

So AD is going to be later on. And AD is also finished enrollment.

Yes.

Yes. But the data is going to be later in the year. So can you talk about the trial design there?

It's actually quite similar to the PN study. It's a randomized placebo-controlled study looking at the same doses of barzolvolimab as we looked in the PN versus placebo. The endpoint there is -- the primary endpoint is the percent decrease in the peak pruritus score at 16 weeks because that study we did similar to others, 16-week placebo-controlled period, 16-week active and then 16-week follow-up.

And that's also 120 or did it overenrolled...

It overenrolled. It was 131, I believe, the final number overenrolled a little bit.

And here, you're actually looking at itch and then secondary endpoint is skin clearance.

Yes, correct.

What -- and so where does -- where do you think this fits? Because the endpoint is a little different than, let's say, a JAK or a Dupi endpoint, which is primary is more skin clearance first.

No. So we chose -- the reason we chose the itch endpoint was because we -- that's what we felt most confident about based on the PN data. So we thought itch, we have a better idea. But we certainly included all the other ones as secondary endpoints. And again, going ahead with a future trial, we would look at all the data and decide what was the most relevant thing for the primary endpoint.

Yes. So you asked about where it would fit. So we -- it's an all-comer study. But where we think we would fit would be the IL-4, IL-13 failures, but before you get to the JAKs.

Before you get to the JAKs.

Yes.

I mean the activity on itch can also be a differentiator. What percentage of patients have severe itch or moderate to severe itch?

Patients had to have -- they had to have an itch score of greater than or equal to 5 at entry. I don't -- we don't yet have the demographics for everybody enrolled.

Still blind. Yes, still blinded.

Okay. Okay. Well, lastly and very important is the stem cell factor TSLP bispecific. And your Phase Ia, you started in December of '24. You had positive SAD data showing about an 18-day half-life, no immunogenicity, fairly clean safety. That was a single IV dose, and now patients are enrolled in the MAD, right? So we're in Part 2 now. And I think data is in Q3.

That's correct. Yes. So we will be reporting both on the multiple ascending dose with the IV dosing, but also we are doing a single ascending dose with our subcutaneous formulation, which we've introduced into that trial. So we should have all that data when we report this summer.

And so the subcu, the Part 3 is also going to be the summer. It won't be Q4. So it sounds like it's going to be at the same time.

I believe so.

And that's going to be a SAD.

Correct.

And so the natural question is what's next for that program? Is that going to go into asthma? Is it going to go into AD?

So we have started a proof of mechanism study in asthma. So from healthy volunteers, I think we'll get a lot of data related to the safety profile and to tryptase reductions, which will inform us about mast cells. But we really want to be -- understand what we're doing in patients. Asthma made the most sense because we will get a lot of PD data related to the TSLP side of the molecule, but also we're collecting sputum samples.

We'll really get information on what we're doing at the level of the lungs in terms of inflammation, in terms of mast cells and other really important inflammation markers. So that's happening now. That's going to help inform the broader program. We certainly think pulmonary indications make a lot of sense. for this combination. We're also looking at potentially things like food allergy and a lot of opportunity, I believe, for a drug that inhibits both TSLP and mast cells.

And the sputum sample, did deep lung sputum or just regular sputum...

Lung...

With a bronch or with a swab.

I think this is induced sputum where they essentially are induced to bring up sputum from the lungs.

Okay. And that study just recently started. So it was probably too early to have data this year.

Well, we're not informing about what timing we'll have data, but it is an open-label study. So for us, we hope to be getting data throughout the year in terms of how that's going and helping us inform moving forward.

Well, terrific, team, thanks so much for joining. We appreciate it.

Thank you...

Thank you.