Welcome to the Celldex Therapeutics webcast and conference call. I'll now turn the call over to Sarah Cavanaugh, Senior Vice President of Corporate Affairs, for some introductory remarks. Sarah?
Good afternoon, and thank you for joining us to discuss top line primary endpoint results from our Barzolvolimab program in chronic inducible urticaria. Joining me on the call today are Anthony Marucci, Co-founder, President, and CEO; Dr. Diane Young, Senior Vice President and Chief Medical Officer; Dr. Tibor Keler, Co-founder, Executive Vice President, and Chief Scientific Officer; Dr. Margo Heath-Chiozzi, Senior Vice President of Regulatory Affairs; and Dr. Diego Alvarado, Vice President of Research. Before we begin our discussion, I would like to direct your attention to slide two with respect to important 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 would now like to turn the call over to Anthony.
Thank you, Sarah. Good afternoon, everyone, and thank you for joining us. We are looking forward to talking with you this afternoon about the unprecedented positive top-line results from our phase ll study of Barzolvolimab in chronic inducible urticaria. We continue to be extremely pleased by the consistency of the data, both the impressive efficacy and the favorable safety profile Barzolvolimab has shown across multiple mast cell-mediated diseases. We now have data establishing clinical benefit and safety in two distinct forms of urticaria, chronic spontaneous urticaria and chronic inducible urticaria, both of which support advancement into registrational studies. Earlier this month, we announced the initiation of two of the largest global studies to be conducted in CSU, and based on the results we announced today, we are now planning for the initiation of a second phase lll program in CIndU.
With active phase ll trials, also in prurigo nodularis, EoE, and by year end in atopic dermatitis. Barzol is actively delivering on its significant potential to be a pipeline and a product. We are particularly excited about today's results in CIndU because of what this could mean for patients with this difficult-to-treat disease. This is the first large, randomized, placebo-controlled study to achieve a successful outcome in CIndU. We believe the results we shared today will offer new hope in the disease setting and once again demonstrate that Barzolvolimab has incredible potential to transform the lives of patients with mast cell-mediated disease. This afternoon, we will present the top-line primary endpoint and top-line safety results. We plan to present the full 12-week primary endpoint and safety data at an upcoming medical meeting in the fourth quarter.
After Diane walks through the data, I will update you on the recent and upcoming milestones, and then we will open the call to your questions. Diane?
Thank you, Anthony. As you know, this afternoon we issued a press release announcing positive top-line 12-week data from our ongoing phase ll study in chronic inducible urticaria. Inducible urticaria is a miserable disease. Patients go to great lengths to avoid disease triggers, but many find it impossible to do so and are impacted by severe itching and burning hives or wheals that impair all parts of their lives, their work, their concentration, their sleep, and their social behavior. In this study, we are exploring two of the most common forms of inducible urticaria, cold-induced and symptomatic dermatographism, or scratch-induced urticarias. People afflicted with cold urticaria experience symptoms like itching, burning wheals, and angioedema when their skin is exposed to cold temperatures. It is important to note that cold isn't necessarily what you and I might think of as cold.
Across our studies, we have seen patients where cold can be 65 or even 80 degrees Fahrenheit. Navigating your day-to-day activities, trying to stay above these thresholds to avoid the onset of symptoms is daunting, to say the least. Symptomatic dermatographism is characterized by the development of itchy wheals in response to stroking, scratching, or rubbing of the skin and usually occurs within minutes of the inciting stimulus. Patients can experience this from everyday occurrences like the waistband of their pants, their socks, or their hair touching their neck. Again, not easy things to avoid in your day-to-day life. For these diseases, mast cell activation, leading to the release of soluble mediators, is thought to be the driving mechanism resulting in the hives, wheals, itch, and other symptoms.
There are currently no approved therapies for chronic inducible urticarias other than antihistamines, and unfortunately for patients, very little forward progress has been made over the years, including in recent clinical trials. To achieve the best outcome in chronic urticarias, we believe you need to target the root driver of the disease, the mast cell. Barzolvolimab's unique mast cell-depleting mechanism and long half-life position the candidate as best-in-class, and the consistent positive results we have reported to date across our phase l and phase ll studies in urticaria support this. Before we dive into the data, let me outline the study design as you see on slide three. This study is a randomized, double-blind, placebo-controlled, parallel group, phase ll study designed to evaluate the efficacy and safety profile of two dose regimens of Barzolvolimab in patients with chronic inducible urticaria who remain symptomatic despite antihistamine therapy.
The study also allowed for patients who had prior biologic use. 196 patients across 78 sites in 11 countries were enrolled in two cohorts differentiated by CIndU subtype. This included 97 patients with cold urticaria and 99 patients with symptomatic dermatographism, who were randomly assigned on a 1:1:1 ratio to receive subcutaneous injections of barzolvolimab at 150 mg every 4 weeks, 300 mg every 8 weeks, or placebo during a 20-week treatment phase. Patients then enter a follow-up phase for an additional 24 weeks. If symptoms recur during the follow-up phase, patients have the option to enter an open-label extension to receive additional treatment. The primary endpoint of the study is the percentage of patients with a negative provocation test at week 12, using the Temp Test for cold urticaria and the Frick Test for symptomatic dermatographism.
These tests utilize standardized triggering stimuli to induce local hives and itching. Secondary endpoints, which we will report on later this year, include safety and other assessments of clinical activity, including critical temperature threshold, critical friction threshold, and the Worst Itch Numeric Rating Scale. All patients have now crossed the 12-week time point, allowing for analysis of the primary endpoint by provocation test. Demographic and baseline disease characteristics were well-balanced across treatment groups. In cold urticaria, patients presented with a mean baseline critical temperature threshold of approximately 19 degrees centigrade or 66 degrees Fahrenheit on the Temp Test on initial provocation testing. In patients with symptomatic dermatographism, baseline Frick Test thresholds were an average of 3.6 out of four pins. Clearly, in both settings, these are challenging dynamics for patients to navigate in their daily lives.
Slide 4 shows the primary endpoint, the percent of patients who achieved complete control of their disease as assessed by a negative provocation test. I am excited to share that we've met our primary endpoint in both diseases across both doses. These results are unprecedented. As Anthony said early, earlier, this is the first large randomized placebo-controlled study to achieve a successful outcome in CIndU. Let's look at the data in detail. First, the chart on the left shows the results in cold urticaria. 46.9% of patients treated with 150 milligrams of barzolvolimab every 4 weeks, and 53.1% of patients treated with 300 milligrams of barzolvolimab every 8 weeks, achieved a complete response, which means no hives on provocation, compared to only 12.5% of patients in the placebo group at 12 weeks.
This was highly statistically significant, as you can see, based on the p-values. Second, on the right, we show the provocation results for the patient with symptomatic dermatographism, where 57.6% of patients treated with 150 milligrams of Barzolvolimab every four weeks and 42.4% of patients treated with 300 milligrams of Barzolvolimab every eight weeks achieved a complete response, which again means no hives on provocation, compared to only 3.2% of patients in the placebo group at 12 weeks. The p-values here are also highly statistically significant. So in summary, the results of both diseases are highly positive and most importantly, very clinically meaningful for patients. Turning now to safety on slide five, Barzolvolimab was well-tolerated with a favorable safety profile through the 12-week readout.
The safety profile continues to be very consistent with what has been reported in our data to date in both CIndU and CSU. Most adverse events were mild to moderate in severity. The most common treatment-emergent adverse events in Barzolvolimab-treated patients were hair color changes at 13% and neutropenia at 11%, very much in line with our results in chronic spontaneous urticaria. Importantly, and consistent with our results in prior studies, the rate of infections was similar between Barzolvolimab-treated patients and placebo, with no association between neutropenia and infections. There were four serious adverse events reported in the study through 12 weeks. Two were reported in the placebo group, a rotator cuff tear and weight loss, and two were reported in the Barzolvolimab group. One reported as unrelated to treatment, a bladder surgery. The other was reported by the investigator as treatment-related anaphylaxis.
However, when this case was reviewed by an independent anaphylaxis adjudication committee comprised of three experts, they concluded there was no evidence of anaphylaxis. The adjudication committee further determined that there has only been a single case of confirmed anaphylaxis in the entire Barzolvolimab program to date, which includes approximately 500 treated patients across our completed phase 1 studies and our ongoing phase ll studies in CSU, CIndU, PN, and EoE. This single case is the event we reported last November in our prurigo nodularis study, which occurred in a patient with multiple comorbidities, which likely meaningfully contributed to the severity of the event. The growing body of clinical data continue to consistently position Barzolvolimab as a well-tolerated, potentially life-changing drug for patients whose lives have been controlled for far too long by these diseases of misery.
Before I turn the call over to Anthony to close, in summary, on slide six, I have to say we are very pleased with this outcome for patients with inducible urticaria and for the Barzolvolimab program. Barzolvolimab is the first drug in development to demonstrate statistically significant and clinically meaningful results in a large, randomized, placebo-controlled study in this disease setting, and these data clearly support moving into registrational studies. It is incredibly gratifying to see such consistent results across our studies, and as a physician, I am very excited about the potential opportunity that lies ahead for patients who need much better treatment options. We look forward to presenting the full 12-week results at a medical meeting later this year and plan to work with the health authorities to design a successful registration program, moving us closer to our goal of bringing this potential new medicine to patients.
On behalf of Celldex, I want to thank the patients and physicians who are participating in this study and playing a direct role in helping to make this a reality. Anthony?
Thank you, Diane. As you can see on slide seven, the data we've reported today support our continued broad development of barzol in mast cell-driven diseases. 2024 has been a monumental year for Barzolvolimab and for Celldex. With our earlier results in CSU, we successfully transitioned to late-stage development and are thrilled to have the data to support a second registration program in CIndU. We are now actively enrolling patients across two robust phase lll studies in CSU, and we look forward to meeting with the health authorities and planning registrational studies in inducible urticaria. As I said in my opening remarks, barzol is actively delivering on its significant pipeline and the product potential. With each study, our knowledge base grows and it supports ongoing efforts to explore and prioritize additional opportunities for indication expansion.
To this end, we are making great progress in our phase ll studies in Prurigo Nodularis and EoE, and are working towards the initiation of a phase ll trial in our 5th indication, Atopic Dermatitis, by the end of the year. Over the next few months, we will continue to receive additional important data. We plan to report the full 12-week results from the Phase 2 ClndU study and the 52-week data from our phase ll CSU study at upcoming medical meetings in the fourth quarter. Before we take your questions, I want to echo Diane's comments and thank the patients and investigators that have participated in our studies. We couldn't be more pleased with the results today, and we look forward to carrying this momentum through the end of the year and into additional later on studies. Operator, we're now ready to take questions.
Thank you. If you'd like to ask a question, please press star one, one. If your question has been answered and you'd like to remove yourself from the queue, please press star one again. Our first question comes from Thomas Smith with Leerink Partners. Your line is open.
Hey, guys. Good afternoon. Thanks for taking the questions, and congrats on the data. Maybe just one on the dosing, and obviously, you saw really nice, complete responses across both dose levels included in this study. Could you just comment on how you're thinking about dosing going forward and how you envision incorporating this into a Phase 3 CIndU program? And then I have a follow-up question.
Sure, Thomas.
Yes. Hi, this is Diane. So, you know, as you saw, we used the same doses in this study as we used in our phase ll study in chronic spontaneous urticaria. You know, we think we have two obviously very successful doses in this study. We're gonna be looking at all the data, and you know, but it is- it's possible we could consider a loading dose, as we did in the CSU study. But we're, you know, we're gonna look at all the data that's coming in.
Got it. That's helpful. And then, with respect to the one case of investigator-reported anaphylaxis, could you just elaborate on what happened with this patient? I guess, what was the time course of that event? And then, can you elaborate on what information the adjudication committee reviewed that allowed them to conclude that there was no evidence of anaphylaxis?
Yeah. So it, the event was an event that was characterized by urticaria and respiratory symptoms. The patient was hospitalized. They were treated with epinephrine, with antihistamines and steroids, and recovered. In terms of the, yeah, the adjudication committee reviews all the details of the case and then make an independent determination about and did not feel that this was a case of anaphylaxis.
Okay, understood. That's helpful. And then just with respect to the neutropenia, can you just elaborate on whether you saw any incidents of Grade three neutropenia? And I guess if you're comparing the kinetics of the neutrophils here, anything different from what you observed from the phase two experience? ... in CSU?
So the neutropenia that were grade one and grade two neutropenia, we had a single case in this study of unconfirmed grade three neutropenia. But the pattern with neutropenia is just very consistent with what we've seen in every other study, you know, with the decrease at the beginning, the stabilization with a lot of fluctuation and things like that. So it's really very consistent.
Got it. That makes sense. All right, guys, thanks for taking the questions. Congrats on the data.
Thanks, Tom.
Thank you. In the interest of time, we ask that you please limit yourself to one question and a follow-up. Our next question comes from Yaron Werber with TD Cowen. Your line is open.
Hi, team. Congrats on the data from us as well. Just a question and a follow-up. You know, the question we're getting a lot is about the loading dose, and just given the kinetics of the rapid mast cell depletion and that's consistent and sort of durable up to 16 weeks, the neutropenia obviously comes back a little earlier. What's the rationale for using a loading dose, especially since there's another company in the space that's obviously not looking at it right now, but of course, we'll see what their data is gonna look like? And then maybe secondly, just a follow-up on the anaphylaxis case. Was the patient admitted for respiratory symptoms? Were they on the regular floor? Did they just get regular oxygen? How fast did they sort of recover, and how deep were their symptoms respiratory-wise? Thank you.
So this is Tibor. I'm happy to take the first part of your question. Subcutaneous dosing, you know, delivers the antibody over many days relative to IV dosing. And so, the advantage of loading doses, providing a larger amount in the beginning, really helps drive that response faster and more durably, and then switching to a maintenance-type dosing to maintain that. This is obviously very common for drugs in the types of diseases we're going after. We think for the CSU program, we felt that our analysis suggested this could be of benefit.
We're also using just a flat dose, not dosing based on weight, and there's a very large fluctuation of sizes of patients in these studies, and we wanna ensure that even heavier patients have the ability to get good exposure. Does that answer your question?
Yes. Thank you on that.
Yeah, so the... You know, as I said, the patient really had a combination of respiratory symptoms as well as urticaria. You know, and, and they were admitted to the hospital. You know, and, and as I described, treated. I mean, they weren't, they weren't all hypertensive, so I can say that, you know?
Okay.
He got epinephrine and some steroids, Yaron. That's it.
Yes.
The patient is fully recovered and released.
But they weren't intubated, right? And they weren't in the ICU, they were just getting oxygen therapy?
No, no.
No, no, no.
No.
Yeah. It was, it was not severe. Okay. Thank you.
Thank you.
Thank you. Our next question comes from Eric Schmidt with Cantor Fitzgerald. Your line is open.
Thanks for taking my question, and congrats as well on this unprecedented result. Just maybe one more question on the anaphylaxis. How soon after the infusion did that patient present in the hospital?
It was within days of the subcutaneous infusion.
But not within hours or minutes?
No. Not that they would... No.
Okay. Had the patient had any prior hospitalizations or severe urticarial reactions?
No.
Okay. And then just coming back to efficacy, obviously, a tremendous result with the primary endpoint negative provocation tests. When we see the secondary endpoint data, I assume that there are patients who didn't quite achieve a complete response but still got benefit from the drug, similar to maybe what you've shown in the past?
Yeah, we'll show that data at the medical meeting, Eric. I mean-
Yeah
The data came in over the weekend, so.
Yeah, this is the primary endpoint was complete response, but we'll be looking at, you know, partial response and, you know, mean change and all, and a whole variety of secondary endpoints.
Okay. Thank you.
Yep. Thank you, Eric.
Thank you. Our next question comes from Yichen Suneja with Guggenheim. Your line is open.
Thank you for taking my question. So could you articulate how consistent was the result in naive versus exposed patients? Did you have any Xolair-exposed patient in this study? How would you characterize the onset? And also, if you can maybe put these data in context, what do we see with Xolair in this similar setting? Our sense is that somewhere around 40%-45% is what we get with Xolair. But curious to hear from you, how do you put these data in perspective? Thanks.
Yes. I will say we're still analyzing all the data in detail. I will say that it was only a small percentage of patients on this study that had received prior Omalizumab, in contrast to the CSU study, which was about 20%. But we are, you know, digging into all that individual data, so I'll be able to talk about that.
Yeah, it was a handful of patients, probably seven patients, that had prior OMA. And based on those small numbers, the responses were the same percentages.
In terms of the data with Xolair, you know, there were two small investigator-initiated studies that were done in cold urticaria and symptomatic dermatographism. So, the cold urticaria study was 31 patients total. And the responses there were 50% complete response at 10 weeks with 300 milligram, 40% at 10 weeks with 150 milligram, and 0% with placebo. And then in the symptomatic dermatographism, by Frick test, it was 53% complete response at 300, 44% at 150, and 11%. But this is, you know, they're smaller studies, and it's observed data, you know, without the non-responder indication, so.
Got it. Thank you. One more clarification question. So with regard to the phase lll program in CIndU, you are considering of using a loading dose, or, or will it be anything similar, or will it be, different than CSU? And then what is the regulatory requirement? Like, how many studies or how many patients?
We're gonna look at the data set and see if we would use a loading dose. You know, as we said, this is a sub-Q study. It's, you know, it wasn't a weight-based study. It was a flat dose, and we just need to look at the data. When we have that conversation with the healthcare authorities, we'll certainly look into it.
And then in terms of the regulatory, you know, as you know, there is not a regulatory precedent. So, you know, what we plan to do once we have all the data from this study is to, you know, have a discussion with FDA and align on, you know, the study that we can do to lead to registration.
Thank you. Our next question comes from Roger Song with Jefferies. Your line is open. Roger, if your telephone's muted, please unmute.
Oh, sorry. Can you guys hear me?
Yep, we can hear you.
Awesome. Yes, congrats for the data, and thank you for taking the question. Quick questions related to the endpoints. Understanding the cold and SD in many different ways to do the provocation tests. So maybe just how validated those tests are, how much discussion you have already with the regulator or your advisor to have the confidence those tests will be used in your phase lll registration study? Thank you.
Yeah. So that's part of the discussion we need to have. You know, they've really been validated as diagnostic tests. You know, they're being pretty widely used in terms of kit following patients and things like that. But it's definitely part of the discussion we need to have about, you know, these provocation tests. You know, the other thing that was used, but not successfully, was the ice cube test, which is what Dupixent used as their provocation test. So, you know, we're gonna look at provocation tests as well as patient-reported outcomes and sort of decide the best way to approach this.
Yeah. Well, Roger, to your knowledge, both Xolair and ligelizumab studies used these same provocation tests.
Got it. Thank you. And maybe a quick follow-up question is related to the, you know, thank you for giving us some, the small SIT study related to Xolair. But just curious about the real-world use for Xolair, maybe even Dupixent, for the, CIndU patient population. Do you see the difference, compared to CSU? Because we don't have too many drugs, having real, real positive study, in both indications.
So real-world use of Xolair, I can't really comment. I can just tell you that on the study, those that were refractory were, you know, OMA refractory, and they were a very small number. It was less than 10 patients that even had prior biologic of 196 patients on this study. So we don't think that there's wide use, and that's why we think that this is a great opportunity for us, for this data to hold up, that we would be frontline in both CSUs.
Got it. That makes sense. Thank you.
Thank you, Roger.
Thank you. Our next question comes from Sam Slutsky with LifeSci Capital. Your line is open.
Hey, good afternoon, everyone. Thanks for taking the questions. Just two for me. I guess first, anything to say on the impact of tryptase between the two dose levels tested and whether it stayed suppressed for the entirety of the dosing intervals or bounced around a bit between them?
... Hi, this is Tibor again. We're still doing the analysis on tryptase and the other PD markers. We believe what we're seeing so far is consistent with our previous studies of, you know, pretty profound and durable decreases in tryptase, but, you know, we still have a lot of work to do on that.
Okay. And then for my follow-up, just in terms of, kinetics of response in the study, did you see the overall response rate continue to improve to week 12, or was it more of a quick response that stayed, through week 12?
So we'll be, you know, showing the kinetics of response, you know, when we get all the data, and later at the medical meeting. So I think we'll look at that in more detail later.
Okay. Thank you.
Thank you. Our next question comes from Andy Chen with Wolfe. Your line is open.
Thank you for taking the question. So just thinking about, if you can replicate this data in phase lll, can you talk about what would drive competitive dynamics versus Xolair, when you're on the market? Is it on-label versus off-label? Is it safety? Is it convenience? What are these factors? And if you can rank order these factors, that would be great. And then I have one follow-up. Thank you.
Yeah. So I think in the U.S., I certainly think this would be the only approved drug if, if it's, if everything maintains. So obviously, we would get the label, and we would be treating first. In Europe, you know, if you don't have an approved product in the indication, you don't get reimbursed at all. So I think that, if the phase III results hold, we would have the frontline positioning, and be the, you know, only drug approved in that area. So I think that that's how it sets up. And, you know, certainly based on the data we see today, we don't see any reason why they would rather go to Xolair than us.
Yeah. And just as a follow-up, on the single anaphylaxis case that was later adjudicated not to be not an anaphylaxis, can you talk about maybe historical precedents with maybe another drug that where something like this similarly has happened, and then it hasn't been a concern later on with the FDA or the label?
Well, so yeah, so first of all, you know, adjudication committees are very commonly used, in, in studies in these kind of indications. And adjudications are really used in cases like this, where, you know, if anaphylaxis is something which, you know, has multiple components to it. And, and so you use an adjudication committee to make an independent assessment by experts, so it takes out the, you know, the, the bias and the differences between investigators, and interpretation. So there's a lot of precedents with having, you know, adjudication committees look at, anaphylaxis endpoints. And it's really an independent assessment that, you know, FDA can look at. So, you know, they'll, they'll see, you know, what the investigators say, and what the independent committee say.
So, you know, I think there's a lot of precedent for this. You know, in the end, FDA looks at all the totality of your data, and that's really what determines, you know, what, how the product is labeled.
Mm-hmm. Thank you.
Thank you. Our next question comes from Alex Thompson with Stifel. Your line is open.
Hey, thanks for taking our question. I guess a question on the placebo responses you observed across both groups. I wonder if you could comment on, you know, your expectations for placebo response here and how they compare to what you saw, and kind of the difference between what we saw in, cold urticaria versus symptomatic dermatographism, and then maybe implications for powering in phase lll. Thanks.
Yeah. So, actually, we had estimated a 10%, a 10% placebo response rate. That our sample size was based on that. But, you know, we were basing it on those early studies that I described for Xolair. There really isn't a lot of data with placebo-controlled studies using these tools. So, you know, we just had to make a guess, and, you know, we're pleased with it, you know, pleased with how the study turned out and certainly the difference between us and the placebo. But I think, you know, so I think, you know, if you use these provocation tests, we use similar assumptions, I think, in phase lll. Did that answer your question?
Andy, did that answer your question? I'm sorry, Alex.
Thank you. There are no further questions. I'd like to turn the call back over to Anthony Marucci for closing remarks.
Thank you, operator. Thank you very much, everyone, for joining us today, and thank you for your time, in our presentation and the great questions. We look forward to catching up later in the year. So have a great day. Thank you.
Thank you for your participation. This does conclude the program. You may now disconnect.