Good day, and welcome to the Celldex ACAAI twelve week CIndU conference call and webcast. At this time, all participants are on a listen-only mode. After the speaker's presentation, there'll be a question and answer session. Instructions will be given at that time. As a reminder, this call may be recorded. I would now like to turn the call over to Sarah Cavanaugh. Please go ahead.
Thank you. Good morning, and thank you all for joining us to discuss the twelve-week results from our Barzollvolimab program in chronic inducible urticaria that were presented this weekend in a late-breaking oral presentation at the American College of Allergy, Asthma, and Immunology Annual Meeting in Boston. 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'd 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'd now like to turn the call over to Anthony.
Thank you, Sarah. Good morning, everyone, and thank you for joining us. We are looking forward to talking with you this morning about the unprecedented positive results from our phase two study of Barzollvolimab 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 Barzollvolimab has shown across multiple mast cell-mediated diseases. The data we will discuss this morning marks the second large randomized placebo-controlled study where Barzollvolimab has met all primary and secondary endpoints, clearly establishing clinical benefit and safety now in two distinct forms of urticaria: chronic spontaneous urticaria and chronic inducible urticaria.
We are particularly excited about the results in CIndU because of what it could mean for patients with this difficult-to-treat disease. This is the first large randomized placebo-controlled study to succeed in CIndU. We believe these results today will offer new hope in this disease and once again demonstrate that barzolvolimab has incredible potential to transform the lives of patients with mast cell-mediated disease. Let me ask Diane to share the data in detail with you. Diane?
Thank you, Anthony. As you know, on Saturday, we presented positive 12-week data from our ongoing phase two study in chronic inducible urticaria. The data were presented by Dr. Jonathan Bernstein in a late-breaking oral presentation at the American College of Allergy, Asthma, and Immunology meeting, and we were extremely well-received by the dermatology and allergy community, who desperately need effective therapies for their patients with inducible urticaria. Dr. Bernstein is a leader in the field of chronic urticaria, and we are pleased to have collaborated with him on the Barzollvolimab development program over the past five years. Turning to slide 3, chronic 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, burning hives or wheals, and angioedema that impair all parts of their lives: their work, their concentration, their sleep, and their social lives. In this study, we are exploring two of the most common forms of inducible urticaria, cold urticaria and symptomatic dermographism. People afflicted with cold urticaria experience symptoms like itching, burning wheals, and angioedema when their skin is exposed to temperatures below body temperature. It is important to know that this isn't necessarily what you and I might think of as cold. We have seen patients where the threshold temperature to develop cold urticaria can be as high as eighty degrees Fahrenheit or even higher.
Navigating one's day-to-day activities, trying to stay above these thresholds to avoid the onset of symptoms, can be a daunting challenge. Symptomatic dermographism 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 form 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. As outlined on the bar chart and the table to the right, not surprisingly, patients with inducible urticaria also report high rates of mental health comorbidities, including anxiety and depression, as they struggle with a disease they feel rules their lives. They also report high medical resource use, including visits to their primary and specialty care physicians and the emergency room, and higher than average hospitalizations.
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. Most recently, dupilumab was determined to be ineffective in cold urticaria in a global phase 3 study, reporting no difference between the drug arm and the placebo arm for the primary endpoint at 24 weeks. Omalizumab has only been tested in small investigator-initiated studies in CIndU. In these studies, efficacy was assessed at 10 weeks, with return of disease noted by week 16.
To achieve the best outcome in chronic inducible urticaria and to offer patients disease relief, we believe you need to target the root driver of the disease, the mast cell. Barzolvolimab's unique mast cell-depleting mechanism positions it as best in disease, and the consistent positive results we have reported to date across our phase 1 and phase 2 studies, including now the phase 2 CIndU data, support this. Before we dive into the data, let me review the study design, as you see on slide four. This study is a randomized, double-blind, placebo-controlled, parallel group, phase 2 study designed to evaluate the efficacy and safety profile of two dose regimens of Barzollumab in patients with CIndU who remain symptomatic despite being on a stable regimen of antihistamine therapy, which can be up to four times the labeled dose. The study also allowed for patients who had prior biologic use.
Patients had to have a positive provocation test, TempTest for cold urticaria, and FricTest for symptomatic dermographism, and they had to have an Urticaria Control Test less than twelve, indicating that their urticaria was not well controlled. One hundred and ninety-six patients across seventy-eight sites in eleven countries were enrolled in two cohorts differentiated by CIndU subtype. This included ninety-seven patients with cold urticaria and ninety-nine patients with symptomatic dermographism, who were randomly assigned on a one-to-one-to-one ratio to receive subcutaneous injections of Barzollvolimab at one hundred and fifty milligrams every four weeks, three hundred milligrams every eight weeks, or placebo during a twenty-week treatment phase. Patients then enter a follow-up phase for an additional twenty-four weeks.
The study also includes an open-label extension phase that allows patients with symptoms during the follow-up phase, including patients who were on placebo during the twenty-week treatment phase, to receive active study drug for up to twenty weeks. The data we will discuss today are from the primary analysis, which was conducted at twelve weeks. Slide five outlines patient baseline characteristics. There are several things I'd like to point out on this slide. First, if you look across the treatment groups, this is a very well-balanced study. Second, patients on study had significant inducible urticaria symptoms, and they'd had these symptoms for a long time, with means ranging from five to eleven years. In cold urticaria, patients presented with a mean baseline critical temperature threshold of approximately nineteen degrees centigrade or sixty-six degrees Fahrenheit on the TempTest on initial provocation testing.
In patients with symptomatic dermographism, baseline FricTest thresholds were an average of 3.6 out of 4 pins. Clearly, in both settings, these are challenging dynamics for patients to navigate in their daily lives. The UCT score at baseline tells this same story, reflecting poorly controlled disease across all cohorts. We think these factors further speak to the strength of the data. As I will detail in a moment, we have achieved an exceptional outcome in a well-balanced study in a severely impacted patient population. Slide 6 shows the patient disposition. Of the 196 patients that were randomized, 3 patients were not treated, resulting in 193 patients being included in the modified intent-to-treat population used to evaluate both safety and efficacy.
90% of patients on study completed the 12-week treatment period, with more patients on the placebo, 14%, discontinuing than the Barzollumab-treated groups at 8%. Discontinuations were primarily associated with patient decisions and factors that are reported as Other, which include, for example, patients moving, coming off treatment because they didn't meet study eligibility requirements, difficulty navigating the demands of participating in a study, et cetera. The rate of discontinuations associated with an adverse event were low and balanced between the Barzollumab and placebo arms. Slide 7 shows the primary endpoint, the percent of patients who achieved a complete response as assessed by a negative provocation test, the TempTest for cold urticaria, and the FricTest for symptomatic dermographism. I am excited to share that we met our primary endpoint in both diseases across both doses. These results are unprecedented.
As Anthony said 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, given that this is the primary endpoint of the study, we assess complete response here using the most conservative approach, non-responder imputation, which means if patients on study did not have a measurement at week 12, they were counted as a non-responder. The chart on the left shows the results in cold urticaria. 46.9% of patients treated with 150 milligrams of Barzollumab every four weeks, and 53.1% of patients treated with 300 milligrams of Barzollumab every eight 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 patients with symptomatic dermographism, where 57.6% of patients treated with 150 milligrams of Barzollumab every four weeks, and 42.4% of patients treated with 300 milligrams of Barzollumab 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 primary results in both diseases are highly positive and most importantly, very clinically meaningful for patients.
As we saw in CSU, the strength of these data is supported by the fact that this study also met all its secondary endpoints, setting Barzollvolimab in a class of its own in CIndU. Let's look at the other endpoints. Slide eight shows a full responder analysis that looks at both complete and partial response. Partial response in ColdU requires at least a four-degree Celsius improvement on the TempTest, and in SD, requires at least two-pin improvement on the FricTest. Up to 75% of patients with cold urticaria and 67% of patients with symptomatic dermographism experienced a clinically meaningful, complete or partial response. There is a high degree of statistical significance across all of the Barzollvolimab dosing groups compared to placebo.
The data on slide nine shows the improvement that patients on Barzollumab experienced in their critical temperature and friction thresholds at twelve weeks, a key secondary endpoint. In the day-to-day life of a patient, this means you are moving the baseline threshold at which patients develop hives, so they can tolerate colder temperatures and more pressure on their skin without resulting hives. Again, patients on Barzollumab experienced clinically meaningful and highly statistically significant changes here. In cold urticaria, patients experienced an improvement, which in this case, is a reduction in their critical temperature threshold of approximately nine degrees Celsius, or almost fifty degrees Fahrenheit, versus point three degrees Celsius, or about thirty-two degrees Fahrenheit for placebo. In symptomatic dermographism, patients improved between two and a quarter to two and a half pins versus not even a single pin for placebo.
These are very meaningful differences that can dramatically improve the day-to-day lives of patients. On Slide 10, you see the time course for the improvements in critical temperature and friction thresholds. These improvements are clearly rapid and sustained over the 12-week period. They are being documented at the first clinic visit post-dosing, which occurs at 2 weeks, where patients undergo repeat provocation testing. These outcomes are also supported when we look specifically at itch. On Slide 11, we show the results of the changes in worst itch NRS provo, which assesses the worst itch that patients experience associated with their provocation test. Here again, patients reported a rapid reduction in itch at their first assessment appointment, and you can see, looking at the curves, that this reduction continues to improve over the 12-week treatment period. Slide 12 shows urticaria control test results.
This is a validated patient-reported outcome tool that asks patients questions about their symptoms, their quality of life, and how treatment is working for them on a monthly basis. At week twelve, many patients on Barzollvolimab achieved complete response, defined as a UCT score of sixteen, up to almost 38% in cold urticaria, compared to just 3% for placebo, and almost 35% in symptomatic dermographism, compared to 0% for placebo. Looking at well-controlled disease, defined as UCT greater than or equal to twelve, almost 70% of patients on Barzollvolimab reported well-controlled disease across both indications, compared to approximately 30% of patients on placebo. Again, highly statistically significant and clinically meaningful results. In summary, across all primary and secondary efficacy outcome measures we evaluated on the study, Barzollvolimab demonstrates clinically meaningful benefit and clear superiority compared to placebo at twelve weeks.
This adds further validation that targeting the root cause of the disease, the mast cell, offers the greatest opportunity for patients with CIndU to experience clinical benefit. Importantly, Barzollvolimab was also well tolerated by patients on study. If we turn now to safety on slide 13, Barzollvolimab demonstrated a favorable safety profile through 12 weeks of treatment. 98% of treatment-emergent adverse events were mild to moderate in severity. 66.7% reported as Grade One, and 31.7% reported as Grade Two. As we have seen in our other studies, the most common events are on-target effects of KIT inhibition and are expected to be reversible. The most common treatment-emergent events in Barzollvolimab-treated patients at 12 weeks were hair color changes in 17 patients, or 13%, with Grade One events reported for 15 patients and Grade Two events reported for 2 patients.
We have included pictures of representative hair color changes from this phase 2 study on the next slide. The picture in the middle was reported as a Grade Two event, and the other pictures were both reported as Grade One events. As we have shown before, these changes are observed as areas of hair lightening on the head, face, and/or body. They are reversible upon treatment cessation. Neutropenia was reported in 13 patients, or 10%. Seven were Grade One, and six were Grade Two events. Importantly, and consistent with our results in prior studies, these events are transient, and the rate of infections was similar between Barzollumab-treated patients and placebo, with no association between neutropenia and infections. There were 5 patients who discontinued on study due to adverse events, 3 on Barzollumab and 2 on placebo.
As we discussed in July when we reported our top-line results, there was one treatment-related serious adverse event that resulted in discontinuation. A patient on 300 milligrams developed hives and reported chest tightness and was hospitalized, treated, and fully recovered. The patient was noted to have normal oxygen levels and vital signs. We had the event reviewed by an independent adjudication committee comprised of three experts, and they concluded there was no evidence of anaphylaxis. On 300 milligrams, a patient discontinued for Grade Two neutropenia because her urticaria symptoms were persisting at that time. On 150 milligrams, a patient entered the study with active urticaria and angioedema, which persisted on the study. About three weeks after her second dose, her symptoms worsened, and the patient discontinued.
The patient did not have a response to treatment, and we believe this event is the patient's underlying disease. We saw a similar adverse event leading to discontinuation in the placebo group in a patient who experienced swelling of the tongue and paresthesia or burning of the mouth. The second discontinuation in the placebo group was a patient with cystic acne and ulcers in the mouth. Overall, the growing body of clinical data continue to position Barzollumab with a very positive benefit-to-risk ratio as a well-tolerated, potentially life-changing drug for patients whose lives have been controlled for far too long by these diseases of misery. The most common treatment-related adverse events are KIT-related effects, which are mostly mild and expected to be fully reversible, and the rate of discontinuation associated with these events is low.
The emerging efficacy data support that sustained KIT inhibition with Barzollvolimab results in unprecedented, highly statistically significant, and clinically meaningful disease control, including complete response, which is the goal for patients and their physicians. Before I turn the call over to Anthony to close, in summary, on slide 15, I have to say we are very pleased with this outcome for patients with inducible urticaria and for the Barzollvolimab program. Barzollvolimab 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. The study met all primary and secondary endpoints with statistical significance, including high rates of complete and partial response. Improvement was marked and rapid across multiple endpoints and was sustained through the 12-week period. Barzollvolimab was also well-tolerated, with a safety profile consistent with previous studies.
As we look across the full treatment period of twenty weeks, the data continue to be exemplary, and the safety profile remains the same. We look forward to working with the health authorities to design a successful registration program, moving us closer to our goal of bringing this potential new medicine to patients. In closing, 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.
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. I also want to again recognize Dr. Marcus Maurer, who played such a leadership role in advocating for patients with inducible urticaria and encouraging drug development in this space. I know he would be thrilled that patients are one step closer to potentially having a new treatment option. Anthony?
Thank you, Diane. I want to echo Diane's gratitude and thank the patients and physicians who are participating in this study. I also share Diane's thoughts on Dr. Maurer. When Celldex first began to explore mast cell-driven diseases, Marcus was instrumental in helping us grow our understanding of these indications and how significantly patients are impacted. The goal of drug development in this space isn't to provide a treatment that helps a patient tamp down their urticaria when they aren't successful at avoiding their triggers. It's to fundamentally change their trigger threshold and allow them to enjoy a full and rich life that isn't governed by a strict set of rules and precautions at every turn.
I remember Marcus telling us about a patient with cold urticaria who participated in our phase one study and came to the clinic so excited because she had been able to drive her car with the window rolled down, and that she had eaten ice cream the night before, something she hadn't done in years. He talked about patients with symptomatic dermographism who couldn't wear socks or pants with a belt. It's easy to take these things for granted in our lives, and I do as well, but I think if you know how to meticulously plan every aspect of your day, to live your life, to avoid your triggers, many of which, when it comes right down to it, are just unavoidable.
The data we discussed today gives me great confidence that Barzollumab can help these patients not just manage their disease, but hopefully regain control of their lives. We believe executing a phase 3 program in CIndU and assuming positive data, pursuing approval in CIndU will be important for these patients, their families, and their physicians. There are conservatively more than 270,000 patients with inducible urticaria in the U.S. and EU5. We plan to address the two largest subtypes, cold and SD. On its own, these markets are sizable.
We have great confidence, given the rigor of our phase 2 study, that we can repeat these results in phase 3 and become the drug of choice for these patients who want to regain control over their lives with a fast-acting, durable drug that offers meaningful opportunity for complete disease control. We look forward to working with the regulators to chart the path forward here, and we'll keep investors updated as we do. With that, I know it's a busy morning, and I want to thank you all for joining us. We look forward to taking your questions and letting you carry on with your day. 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 one again. We ask that you limit yourself to one question. Our first question comes from Thomas Smith with Leerink Partners. Your line is open.
Hey, guys. Good morning. Thanks for taking our question. Good morning, Tom and congrats on the data. Yeah, just, Thank you. One question, and, if I could sneak in a follow-up after that, that would be great. Just first on efficacy, it looks like you're having a really rapid onset of effect here at week two. I wonder if you could provide some updated thoughts on how you're currently thinking about the Phase III trial design and whether there's an opportunity to take a look at earlier time points so you can better define that onset of effect.
So in terms of the Phase III trial design, we need to have discussions with the FDA as far as, you know, appropriate endpoints for that study. You know, we're certainly thinking of a randomized placebo-controlled study. We're looking at, you know, both forms of inducible urticarias, and we do think that we have positive doses, you know, for both doses in this study. So we would certainly consider both those doses, and we are considering adding a loading dose as we've done with our CSU study. You know, and certainly there's you know, the possibility of looking at earlier time points in the study.
Yeah, but remember, in this study, Tom, we did the time points at two weeks, which was their first visit. So we're really getting that rapid response that we're looking for. I think that going forward with the Phase III, we're just looking to see, because we need to look at weights, we need to look at a bunch of different things, whether it's appropriate to do a loading dose. But we're perfectly happy with the rapidity of the response, the durability that we're seeing. And, again, I don't think we would need to look any earlier than two weeks because that's when we're looking at their first assessment.
Got it. That makes sense. And, yeah, just, with respect to the data that's still being generated in this study, I know it's designed as a twenty-week randomized period, and then you're following the patients out for another twenty-four weeks. Can you comment at all on anything that you're seeing, both in terms of efficacy or safety out beyond that twelve-week time point that was presented here? Do you have any data out at the twenty-week time point or out into the follow-up period at this point?
Yeah, so the data beyond 12 weeks is not yet cleaned, and we haven't analyzed it, but we're certainly following the data. And I can tell you that we're pleased with what we're seeing, you know, both from an efficacy and a safety standpoint.
Got it. That's helpful. All right, guys, thanks for taking the questions. Congrats on the data.
Thanks, Tom.
Thank you. Our next question comes from Yaron Werber with TD Cowen. Your line is open. Yaron, if your telephone's muted, please unmute. Our next question comes from Yatin Suneja with Guggenheim Securities. Your line is open.
Hi, good morning. This is Eddie on for Yatin. Thanks for taking our questions and congrats on the data.
Thank you.
Looks like a lower number of the omalizumab-experienced or refractory patients were enrolled. Did those show consistent efficacy, and were there any Dupixent-experienced patients in the study? Any added color on that would be helpful, even though I know the numbers were lower. And then it looks like the discontinuation rate was a bit higher in SD versus the cold. Is there any explanation for that biologically, and could it impact the phase 3 design at all? Thanks.
So in terms of the omalizumab-treated patients, we did see a lower incidence of OMA-treated patients. We think that's because it's not approved in this indication. And in the countries that we were doing the study, a lot of them, you know, the patients may not have had access to omalizumab as they might in the US. But we were very encouraged by the data in that small number of patients, and very consistently to what we've seen with other studies, we do see responses in OMA-experienced and particularly OMA-refractory patients. We had nine omalizumab-treated patients on the study. Six were omalizumab refractory, and two of those were in the placebo group and had no response. Two were in the one fifty or the, and two were in the three hundred group. Out of the Barzollvolimab-treated patients, three out of four had response, complete response on the study.
Yeah.
And then in terms of dupilumab, interestingly, we had four patients who had prior dupilumab, all in cold urticaria, and three out of four of those patients had responses. Complete responses, yeah.
Very helpful. Thank you.
Oh, I'm sorry.
And then we asked about the discontinuation.
Yeah, I don't have – I don't really have a reason why the discontinuation rate was higher in symptomatic dermographism at this time. I mean, you know, the most common reasons for discontinuation, you know, were common to both, you know, which is things like, you know, patient decision just to get off the study, moving, you know, patients not being eligible for the study. But there – I don't, you know, we don't really-
Yeah see yet a difference why that rate should be different.
Gotcha. And then just finally, is the placebo sort of in the range you expected? And then how should we expect that to sort of evolve as the study matures to sort of later time points? Thanks.
So there isn't that much published actually in these indications that we could know precisely what the placebo was going to be. The placebo varies according to which tools you're looking at. But I will say we were extremely pleased with the placebo rates that we got in the study and the fact that, you know, we have differences from placebo in virtually all of the endpoints, which is very encouraging.
Thanks again.
Thank you.
Thank you. Our next question comes from Kristen Kluska with Cantor Fitzgerald. Your line is open.
Hi, good morning, everybody, and congrats on these updated data. Looks very good. So I wanted to ask more about the current commercial dynamics and reimbursement piece. Obviously, this is a different ballgame than CSU, given there are no current approved therapies here. So maybe can you remind us, first on reimbursement, how Xolair is used, whether it's reimbursed in current regions, and also how that might impact the positioning of where Barzollvolimab could be utilized, if approved? Thanks again.
Yeah, Kristen. So in the U.S., they are using it off-label. I do believe that they are getting reimbursed to a lesser extent, but also, we also think that they would also have probably some CSU on top of what they're having. In Europe and other parts of the world, we know in Europe that they won't get reimbursed. In fact, in Europe, you have to have an approval of the indication, otherwise you don't get reimbursed. Then there are other parts of the world where Xolair is not even approved, so there's really no ability for those patients to get it for CIndU. Does that answer your question?
Yes. Thanks very much.
Thank you. Our next question comes from Yaron Werber with TD Cowen. Your line is open.
I'm on, yeah. Hey, it's,
Yaron, we can hear you.
Yaron, sorry.
Okay, great.
Hi, Yaron.
Sorry for the confusion on the name. So I've got maybe just a couple of questions that are interrelated. The first one is, when you look at the slides, because we get questions on this a lot on the hair color changes, it looks fairly mild and sort of very diffuse. Can you maybe talk about what's the cadence of hair color change? Does it happen early and sort of is sustainable? And the picture that you're showing, is that sort of typical of what patients see? And then maybe secondly, and I know you're going to give more guidance on your year-end call, but for the EoE data, the phase two proof of concept, is there a chance to get that data next year? Thank you.
Sure.
Yeah, so in terms of the hair color changes, they, you know, start occurring several weeks into treatment. I think the pictures that we have are representative of the kinds of things we see, which, as we've said, are, you know, mild hair lightening. You know, it can be on the head, on the body, in the beard, or whatever. So I think those pictures are
Very indicative
are typical of what we've been seeing. And as we've said, you know, they do reverse off of treatment.
Yeah. And again, those pictures are very indicative of what's been seen in the clinic, and you can just see very, very light pieces of hair being changed. And you know, what we also see that a lot of these patients are in their forties, fifties, and even sixties. So, they're being told, the PIs are being told to look for it because it is a KIT-targeting mechanism. So, you know, but there's really no concern. Nobody gets off study because of this stuff for the most part. And as far as the EoE study, Yaron, we should be completing that in the first half, and we'll present those data at the appropriate conference in the second half of 2025.
Okay, great. And but I don't know if you can hear me, but just the hair color changes, so it's this is sort of consistent with what is seen even at a year. It's not as if the whole hair everywhere is changing white?
Yeah, very consistent, what you see even longer term.
Yeah, correct.
So it's very subtle, and it seems consistent from what you see early to what you see later on.
Correct.
Okay, great. Thank you.
Thank you.
Thank you. Our next question comes from Sam Slutsky with LifeSci Capital. Your line is open.
Hey, good morning, everyone. Thanks for taking the questions. Just on Phase III for CIndU, can you just discuss the expectations for how easy it is to enroll a CIndU study versus CSU? And then any insights from your experience enrolling the phase two studies, both in CSU and CIndU, whether it's patients per site and kind of so forth, as you think about that timing?
Yeah. So, I think, you know, CIndU is a less common disease than CSU, and we have different subtypes you need to select. But, you know, beyond that, it wasn't really that difficult to enroll the study. You know, we tend to involve the same investigators in our CSU studies as well as our CIndU studies.
Yeah. Yeah, so Sam, you know, we had a certain time limit on this study that we thought we could accrue it on, and we beat that by several months. I'm sure these data will be very, very helpful to us as we go into the Phase III part of the accrual. Cold does have a little bit more seasonality to it, but, you know, as Diane said, we had no problems accruing the study or getting people interested, or PIs interested, for that matter.
Okay, and then
On top of that, the Phase III is gonna be a lot smaller than the CSU study, so we don't think it's gonna take any more time than the phase two did.
Got it, and then do I have time for a follow-up?
Yeah. Sure.
Cool. Just, regarding SD and cold, obviously, they're the most common. Can you just remind me what portion of CIndU they make up? And then, I guess, as you think broader, any plans to expand into whether it's cholinergic or other subtypes?
Sure. So, SD makes up anywhere between 60%-65% of the CIndU, and cold makes up anywhere between 15%-20%. So the vast majority of them are SD and cold, followed by cholinergic, which is probably another 10%-15%. So just between the three of them, it's probably closer to 90%-95% of all CIndU.
Okay, thank you.
Yep.
Thank you. Our next question comes from David Lebowitz with Citi. Your line is open.
Thank you very much for taking my question. Could you offer perspective on what the urticaria of these patients might experience versus the more run-of-the-mill experience that typical individuals have probably all experienced in terms of severity, in terms of edema, and the types of effects that would make, that drive them to be going to higher level therapies?
The patients can experience, you know, that they can experience, you know, very severe urticaria associated with their triggers, and, you know, it's not relieved by antihistamines. The cold urticaria patients, in particular, can have, you know, in addition to the severe urticaria and angioedema, can actually have, you know, very severe systemic effects as well. I think that's one of the underrecognized things about CIndU, is that there is a patient population that is very, you know, severely impacted and, you know, have modified their lives to significant degrees to avoid their triggers, and those would be the patients that, you know, would be appropriate for biologic care. Typically, how effective is the effort to avoid triggers in keeping symptoms at bay?
I mean, it really depends on the individual patients. For, you know, for some patients, it may be possible, you know, if you have cold urticaria and you live in a warm climate, for example. But, you know, for other patients, the nature of their disease is such that, you know, it really is pretty hard to avoid their triggers.
Thanks for taking my question.
Thank you, David.
Thank you. Our next question comes from Roger Song with Jefferies. Your line is open.
Thank you. Congrats for the data, and thank you for taking the question. This is Roger from Jefferies. So quick questions. One is, you have a couple of grade two neutropenia, but you only have one leading to the discontinuation. Just curious what that case is different from other grade two neutropenia, why it caused the discontinuation, while other grade two did not? And then also, regarding the data updates, moving forward from this phase two, when and how we should expect to to see the next data update, for example, like tryptase and maybe some biopsy for the mast cell depletion? Thank you.
Yeah, thank you for the question. So the grade two neutropenia that discontinued was a grade two neutropenia, you know, and the patient, but the patient also was not responding. So when it was, you know, time to kind of come in and have lab tests and continue in the study, the patient said, "You know, I'm not responding. I don't wanna bother." So they really, while they did have, you know, grade two neutropenia, the patient decided not to continue in the study.
Data reporting?
Oh, yeah. So the data reporting, we plan to next report on this study after we've completed the twenty-four-week follow-up. So we think that will be sometime in the second half of next year.
Got it. Thank you.
Thanks, Roger.
Thank you. Our next question comes from Rich Law with GS. Your line is open.
Hi, guys. Congrats on the data. How should we interpret the endpoints that you achieved? And how do those translate to quality of life benefits across the daily activities for patients and compared to people without the disease? And then I have a follow-up question.
Richard, I'm sorry, you kind of broke up. Can you repeat that, please?
Yeah. How should we interpret the endpoints that you guys achieve? and how did those translate to quality of life benefits across the daily activity for patients and compared to people without the disease?
So the primary endpoint of the study was the negative provocation test. So the provocation test measure you know what degree of stimulus, in one case, temperature, and in one case, pressure, cause the patient to have hives. And so with the you know cold urticaria test, complete response means that the patients, no matter what their threshold, that was inducing their hives was at the beginning, then they you couldn't induce the hives anymore. So that's you know that means that you shouldn't be able to stimulate the you know you shouldn't be able to stimulate hives. And similarly, for the FricTest, the fact that they were able to reduce the number of pins means that less pressure would be causing the hives on their skin.
So in terms of... So these endpoints, these thresholds, you know, there's data in the literature that they are very relevant to the patient's overall quality of life. In this case, in addition to the provocation endpoint, we also looked at the urticaria control test, and that is a very nice global test that is asking the patient about their day-to-day experiences with urticaria over the past month. So it's asking about their symptoms, how well they feel the treatment is controlling the symptoms, and also their quality of life is included in that as well. So, you know, as you can see, you know, we had very high rates of people achieving well controlled or complete control of their urticaria by that measure. So we regard that as a measure that is reflecting the patient's, you know, overall quality of life and urticaria.
Got it. So, when you say complete response, would that carry over to, like, day-to-day activity, like eating ice cream, swimming, and stuff like that without causing any symptoms?
Yes, it should. That's what we saw in our Phase 1b study, and that's what we're seeing here, is that all the endpoints are very consistent. You know, when you have, you know, a reduction in those provocation tests, you also get improvement of quality of life and control of urticaria day to day.
Yeah. I see. Okay. We're changing the paradigm here. Fantastic. And have you guys analyzed the health economics for CIndU? And what is that like, health economic value for a drug like Barzol? I think you guys put out some numbers in terms of the number of HCP, ER visits, and hospitalization. Just curious to see, like, how, what
Yeah.
How does the drug translate to health economic value?
Yeah, that's a continuing process, Richard. We've done some of it in the U.S. We're going to do the rest of it in Europe, and we should have some more data on that, you know, sometime midyear next year. But we do believe it's very high.
Great. And then just one final question. How do you anticipate the longer-term safety and discontinuation rate look like for CIndU compared to your CSU 52 weeks? Is there any disease characteristics of CIndU that would make you think that the discontinuation could be higher or lower?
No.
No.
No. Like I said, we've taken a look at the unblinded 20-week data. We're very happy with what we see, both from safety and efficacy. We don't anticipate it being much different than CSU, so... but we have to see. We're very encouraged.
Okay. Thanks, guys.
Thank you.
Thank you. Our next question comes from Alex Thompson with Stifel. Your line is open.
Hey, great, congrats on the data. I guess maybe if I could ask a question on the CSU Phase III program. I was wondering if you could provide a little bit of color on how the enrollment there is progressing and whether there have been any instances of anaphylaxis as you've started to dose patients broadly. Thank you.
Sure. So it's too early to be giving any guidance on how it started because we just started during the summer. We are enrolling as we would have expected. We're putting sites on as we would have expected. There have been nothing on anaphylaxis, so, you know, we're just moving forward with this stuff, but nothing to report on anything other than the study is moving along as we have expected and as we have hoped.
Great. Thank you. And then maybe one quick follow-up. I guess, in the CIndU study here, could you comment sort of on your, you know, confidence in tryptase as a biomarker and sort of the broader directionality and magnitude of, of reductions across both dose arms? Thanks.
Hi, Alex, this is Tibor. Sure. As we said throughout this program, we really think tryptase is a remarkable biomarker. I've never come across something that correlates so well with both the mechanism of action, you know, mast cell depletion, as well as with the clinical outcomes. And we've been following tryptase and using it really to guide our decisions in terms of dosing and regimens. And we'll do that here as well with CIndU for determining what would be best to move forward in Phase III. But overall, as we've shown with other data endpoints, tryptase is really shown to be very consistent with Barzoll's effect in terms of rapid and sustained significant, you know, profound decrease in tryptase, and very important to maintain that, you know, that suppression of tryptase.
Great. Thank you.
Andy, are you there? Andy, if your telephone's muted, please unmute.
Hey, guys, it's Chuka on the phone for Andy. Two quick ones from us. So the first one on enrollment. What are your expectations for a phase III versus phase III enrollment versus Dupi and Remi? And then on CSU phase III, you appear to be enrolling from 28 and 41 locations. Would this be all, or will you plan on adding new locations over time? And then what is the total site count in your plan? Thank you.
Okay, so, as far as CSU, we plan on enrolling 1,800 plus patients in the study. Approximately 480 sites across 36 countries, Chuka. As far as our expectations for phase III enrollment versus Dupi and Remi, we'll just go by what we did in our phase II, which we've accrued it in less than 18 months, and we think it shouldn't be anything longer than that because the study is not gonna be nearly as large as CSU. In fact, you know, depending on what we discuss with the FDA, we're looking at a couple of hundred patients in SD and cold. So we think that the timing around that will be very quick, very rapid.
Got it. Thank you.
Yep.
Thank you. And our last question comes from Joe Pantginis with H.C. Wainwright. Your line is open.
Hey, everybody. Good morning, and thanks, and very nice data. So, just quickly, first, to follow up on the kinetics of the response. Obviously, it's about the long-term efficacy here, and you do see a rapid response within two weeks. I was just curious, on the front end, at least, do you have any physician evidence from patient anecdotes that it's working even faster?
Well, they don't visit till the week two, so I don't know that we have any anecdotes. We certainly did capture some earlier data in our phase I study. We certainly expect that patients are responding very quickly. We do know that sub-Q exposure is a little bit slower than IV, but I expect that patients are beginning to experience benefit within days of their initial dosing. But we haven't captured that data, Joe.
No, I understand. No, that's helpful. Thanks. And then my broader question is for Anthony and the team in general. So, to the extent that you want to or can answer, when you look at all of the data releases that you've had, all of which have been positive, whether it's for CSU or CIndU and beyond, there really seem to be two divergent patterns. The first pattern is really the broader positive response that you're getting from the medical community regarding the clinical efficacy and the rapidity of the efficacy.
And the second pattern of response is really on the investment front, you know, that leads to, I'd call it, extra volatility, with sometimes extra focus on the neutropenia, and that's despite all of the, you know, the neutropenia that you're seeing, pretty much staying within the limits of normal. So I'm hoping you can sort of describe the divergent patterns here.
Yeah. I mean, I'll give you my take on it, and then Diane can answer it, too. I mean, so when we get questions about neutropenia, you know, the first thing we're starting to do now is, do you have a question on neutropenia, or do you have a question on the grades of neutropenia? And that usually stops some people in their tracks because they don't understand the difference between a grade one, a grade two, and a grade three. Now, you've seen on most of our studies, many of the neutropenias are grade one, which are basically very, very small drops from normal.
We've only had one confirmed grade three in over three hundred and thirty-five patients treated in our phase II study. So I think that there's a big disconnect, Joe, and that's something that we hope to bridge over the coming months, as we do, you know, conduct more studies and get out more data. So we're gonna look to try to bridge that.
Great. I appreciate that, Anthony. Looking forward to the next steps.
Thanks, Joe.
Thank you. There are no further questions at this time. I'd like to turn the call back over to Anthony Marucci for closing remarks.
Okay, thank you very much, and thanks, everybody, for joining us this morning. We appreciate the early start, and have a great day.
Thank you for your participation. This does conclude the program. You may now disconnect. Everyone, have a great day.