Celldex Therapeutics, Inc. (CLDX) Earnings Call Transcript & Summary

Okay. All right. Good morning, everyone. Thank you for joining us this morning for our presentation from the Quad AI event yesterday. On the dais with me this morning, we have Dr. Tibor Keler, who's our Co-Founder and Chief Scientific Officer; to Tibor's right, we have Dr. Marcus Maurer, who is going to be presenting the data today and has been really involved with our program from Charite. We got Diane Young, our Chief Medical Officer; and Dr. Allen Kaplan, who has given us some time today to be with us and make some comments on the data as well. So before we get going, the obvious safe harbor statement that we'll be making some forward-looking statements today. We always refer everyone to our SEC filings where we discuss our risks and forward-looking statements in more detail. As I said, Dr. Maurer is with us today. He will be presenting the data. He's been very gracious with his time. But I'm also -- he's been very busy. So we want to be very, very cognizant of his time today as well as Dr. Kaplan's. So what I would ask is let us finish the presentation and then we can take the Q&A, this way things are a lot smoother. As I said, Dr. Kaplan is also joining us. He's from the University of South Carolina. And in addition to Tibor and Diane, we have Dr. Margo Heath-Chiozzi with us today. She's our Head of Regulatory Affairs. Diego Alvarado, who is our Executive Director of Research. And you all know Sarah, who's our Senior Vice President of Corporate Affairs. So obviously, we are presenting our data today, and we're very, very excited about that, but we're also very excited about the rest of the pipeline and just some of the events that we believe we'll be hitting this year. So to start with this data today, we'll be talking about that. We also have the PN data, which we will start a Phase II study in the first half of this year. We guided that we would start the Phase III studies in CSU, which is based off the data that's going to be presented today. We would start the Phase IIIs in the summer of 2024. Behind that, we have the Phase II CIndU data in the second half of this year as well as the 52-week data from the CSU study also in the second half of the year, which we'll be presenting. And then also in the second half, we'll be disclosing our fifth indication for barzol. So a lot of work to do, a lot of exciting things that are happening, and we're going to be extremely busy this year. So with that, let me hand it off to Tibor to talk about some of the tox work that's been done. I know we've talked about this with you all in the past, and I think this is the proper setting for us to put this all together and briefly discuss it. Tibor?

Thank you, Anthony. Good morning, everyone. Before we get to our toxicology summary, I just wanted to review why we really feel this is a best-in-class antagonist antibody. Obviously, it is very specific for the KIT receptor and binds with extremely high affinity. But what's -- what really differentiates barzolvolimab from some of the other anti-KIT antibodies is its mechanism of action, which is based on preventing receptor dimerization as opposed to stem cell factor binding directly. And this is a mechanism that we have proven not only through preclinical work, but through direct evidence in patients looking at both the mast cell marker tryptase as well as the depletion of mast cells, which, again, is really unique to barzolvolimab. In addition to that, -- we just -- we hardly ever focus on some of the product profile optimization that we've included in this antibody. It's been very important to do some engineering that both helps the safety profile for the molecule but also extends its half-life. So we've engineered in mutations to the FC domain to really give the molecule a great product profile. And along with that, it's also critical to have a robust manufacturing process and a really good, stable, high-concentration formulation for the subcutaneous administration that we do. And really, barzolvolimab has checked all of these boxes very effectively. So that's really why we think we're best in class. And turning to the toxicology studies that we believe with their completion, we think we have completed the work that we need to do to support our initial BLA. Some of these we've discussed in detail before, so we've completed a number of studies in nonhuman primates where we have dosed up to 75 milligrams per kilogram every couple of weeks for 6 months. This has been done both in adolescent and in mature animals. And the only findings we've seen are things that are expected with KIT suppression. These are some transient mild effects regarding hematologic parameters. We've talked about the diffuse recoverable hair lightning or fur lightening in these animals and, of course, the impact that we have on spermatogenesis, which is scientifically really well understood and completely recoverable. And what's important in these studies where we've looked at reproductive organs very carefully. We have not seen any impact on female reproductive tissues. And this is not just done by the pathologists involved in the study, but we've had that data peer reviewed by experts. So we really feel comfortable with the results we've seen regarding these tox data. The study that we're reporting some new data on today is what's called enhanced pre- and post-natal development study. This is where -- really where you're trying to understand the impacts of the drug on maternal and fetal and infant development, in this case, mothers. As soon as they're recognized to be pregnant, they start dosing those animals, again, at a very high dose, 75 milligrams per kilogram every 2 weeks, and that's for approximately 6 months, so during their entire pregnancy. Importantly, with the mothers, all of the pregnancies were normal. There were no clinical adverse effects in observed at all with the mothers with the exception of the hair lightening that we anticipate with that long-term high dosing. Most importantly, the infants have been born healthy. They have shown no development or growth issues. And this -- they are observed through 6 months of age. We do observe as one might expect that they have varying amounts of white fur and in some cases, some lightening of skin. This just shows how much exposure these -- the fetuses had actually during pregnancy and development. Importantly, again, the reproductive organs while they are relatively immature yet in these infants, there were no adverse findings reported whatsoever with regards to their development. So I'd be happy to answer any questions folks might have in the Q&A, but I really want to turn the presentation over to Dr. Maurer to talk about what we're really here for. Thank you.

Thanks, Tibor. Good morning, everyone. Thank you for your continued interest in this program and in this disease. It's a devastating disease. And I make that point because of a conversation that we had yesterday where someone said and he started his sentence with, "Given that this is a benign disease," and this sort of triggered me to include some slides here that I wasn't going to show on chronic spontaneous urticaria and what it does to people. This is a horrific disease. Don't wish this on anyone. This is a disease that ruins lives, that has patients devastated. They don't function. They don't like themselves. They don't like us because we have very little to offer. They don't function at work, in their families, and their partnerships. They don't sleep well. Their sex life is disturbed, everything in their lives does not work because of this disease. And that's a point, I think, that we really have to make and also bring on board when we develop better treatment options. And it is very difficult to imagine what it feels like to have urticaria. But if you have stinging metals in your country or if you've ever encountered a jellyfish that gives you these burning, stinging wheals. And you imagine that this happens to you every day for years on end, then maybe you start to get an idea of what it is like to have this stupid disease and unpredictably, of course, these wheals come hundreds of them every day. When and where they want, you cannot predict this. And on top of that, up to 70% of patients have recurrent angioedema, swelling of the lips of the genitalia, of the hands, the feet, impairing severely the life of patients. On top of that, chronic spontaneous urticaria often comes with comorbidities, chronic inducible urticaria is one of them. And the severe itch, I'm going to say this is the most severely itchy disease is really what drives people crazy, and sometimes literally. It's horrible to see how these patients suffer for years and years and many do this going through many different treatments, being frustrated by what we have to offer and suffering in all aspects of their lives from this disease. So this is not a benign disease. It is not a benign disease. And we have to realize that patients on average have this disease for 5 to 7 years. That's many hundreds and thousands of days that people are troubled by their itchy wheals and also andreodema. And if it were that we could treat these patients today so that they all have their disease under control, and they could wait very confidently and relaxed that their disease goes into spontaneous remission, where we probably wouldn't be here, but that's not the case. That's not the case at all. Despite having antihistamines and omalizumab available, these are recent data, 80% of patients today do not have their disease under control. And this is measured with a standardized, validated robust outcome measure, the urticaria control test we're having less than 12 points, reflects having uncontrolled poorly controlled disease. So you ask the next 1,000 urticaria patients that come to us or to any one of them, do you have your disease under control with this tool, and 79% of them say, "No, I do not." And you might think that, "Well, if this is new and they haven't really found anyone who could help them, well, that could be understandable." But it is not even people who've had this for 8 years and longer are still not in control of their disease. 72% of patients who have the disease for longer than 8 years, where you might think they must have found a dermatologist, an allergist, a urticariologist who can help them. No. So, this is a devastating situation for patients that we want to change. In part, this comes from not making use of what we have today to the best of our ability. But in a large part, this comes from not having treatments that we can offer to patients who are resistant to the currently available treatments. So I really want you and my colleagues and everyone to understand that this is not a benign disease with a high unmet need. We talk to people who have this for a long time, and most of them have their disease not under control. Enter barzolvolimab, the light at the end of the tunnel, if you might say, the only all-comer treatment that is currently under development. What do I mean? I mean that patients with chronic spontaneous urticaria have different causes of their disease. We know about autoimmunity. We know about auto-allergy, and we don't know about some of the causes that are relevant, but it's clear that there is no one size fits all when it comes to the cause, the underlying cause of chronic spontaneous urticaria. But we also know that no matter what your cause, no matter what your pathogenic pathway, mast cells are needed to translate this pathogenesis into the clinical signs and symptoms. So targeting mast cells as is done by barzolvolimab with a depleting approach is an approach that will and can benefit all patients with chronic spontaneous urticaria. The background, you're very well aware of, we've shared data on chronic inducible urticaria with magnificent results in terms of clinical efficacy. It's really stunning to see that I think we treated 30 cold urticaria patients with different doses. So far, you have 100% complete response. That's amazing because these patients do not respond well to antihistamines, and that's the only licensed treatment option we have for them. So that's really hope and all of my cold urticaria patients who were in this clinical trial,; they call me and they want to be retreated and can't wait for this to be available to them. From that experience in chronic inducible urticaria, we come to chronic spontaneous urticaria, which is similar but different. Both diseases are mast cell dependent. It's similar. Both diseases are driven by the degranulation of mast cells in the skin, a release of proinflammatory mediators that then result in wheals and angioedema. This is how they're similar. But they are different in how mast cells get activated, and they are different to some extent also in how many mast cells are driving the disease. In patients with chronic inducible urticaria, we see the same mast cell numbers as in all of us, normal mast cell numbers. This is not the case in patients with chronic spontaneous urticaria, where you have a variability of increase of mast cell numbers in the skin. Not all of them have increased mast cell numbers, but some of them have double, triple, quadruple or even higher the number of mast cells as we see in healthy individuals or chronic inducible urticaria. So that's one of the differences that we see between chronic spontaneous urticaria and chronic inducible urticaria. And this is why it's, of course, important to study chronic spontaneous urticaria, which was done in this clinical trial. I think most of you are familiar with the data that we shared yesterday. So let me just briefly review for those who may be less familiar that we'll be sharing today the 12-week data of a placebo-controlled approach to chronic spontaneous urticaria, investigating 3 different doses of barzolvolimab. Without going into the details, but if you're interested about the dosing scheme and the doses themselves, I will be happy to review them. Now this is a straightforward chronic spontaneous urticaria study, how? You include patients with chronic spontaneous urticaria. You make sure that they have enough signs and symptoms to measure any change in their clinical disease activity. So they have to have a UAS7 or 16 or higher. For those of you not familiar with the UAS, it's the standard tool to measure disease activity. It comes from a daily documentation of the number of wheals in categories, the daily intensity of itch in categories, giving you 6 points if you have maximum disease activity on that day, 0 points, no wheals no itch, times 7 days a week is 42. So just to put that into perspective, 42 urticaria hell. 0, that's where we want patients to be. They go into this with a minimum of 16 and with a minimum of 8 for the itch component of the UAS, which is half of the UAS7. Good. Okay. So the primary endpoint is the UAS7. As I said, the gold standard, but we also measured itch severity with the ISS7 and wheal severity with the HSS7 secondary endpoint or mean change responder analysis, and there are some exploratory analysis that we will not focus on today. You see the disposition of patients going into the study, randomized and then allocated to the 4 treatment groups where, yes, you have a low rate of patients who discontinued, similar across the 4 treatment arms. And let's go to the results. Now, let's go to the baseline features of these patients. Why? Because I want to show you that these are -- first of all, urticaria patients with classical features of urticaria. They're more often female than male. What I really like about the study is that we're finally getting data from non-white chronic spontaneous urticaria patients, which is very important given that this is a global disease with high prevalence in Asia, high prevalence in Latin America, where we need to understand how patients coming from these geographies respond. So it's good to have a diverse patient population here. But I want to draw your attention to the UAS7. Remember how we said 16 was what you had to go in. Well, patients didn't have 16. They had 30, 30, you see that second half, 30, 31. So this is, if you go again back to 0 to 42, this is all the way here where you don't want to be. This is either, on average, moderate or severe disease activity. They come from a high level of disease activity. And if you turn that around, we talked about the urticaria control tests used in a general population of chronic spontaneous urticaria patients, this means that patients do not have their disease under control. Again, 0 is no control at all in the UCT. 16 is complete control. 12 is where you divide between poorly controlled and well controlled. And they go into the study with 3, 4, so very much on the bottom end of control, very much in the spectrum of poorly controlled disease or uncontrolled disease. Relatively high rate of patients with angioedema, and this is linked to the high disease activity measured with the UAS7. The duration, many years on average. And yes, the rest you can see yourself. But those are some of the key features that I wanted to point out to you. These are the results, and I get excited about this slide every time I show it. This is unheard of. This is the best outcome that we've seen so far in any clinical trial in chronic spontaneous urticaria. And I said the same thing when I first saw the CIndU data where you can't get better than 100%. I hope you all agree on that. And that's what we saw in the CIndU trial. Here, we see a reduction with the 300 milligrams given every 8 weeks, every 8 weeks 300 milligrams of 24 points in the UAS. I want to remind you, again, it goes from 42 to 0. They start at 30, and you have a reduction of 24. That's beautiful. That's really something that, yes, is great. You see a dose response in some extent so that even the 75 milligrams given every 4 week have a better response as compared to placebo. But yes, this is what we expected and are very happy to see it turned out to be the result. The kinetics are beautiful. Why? Because you see a fast response, which is not the most important feature of a drug in chronic spontaneous urticaria, but a very welcomed one. These people have suffered from their wheals from their angioedema for years. And now finally, something works and it works fast. This is great. You can see that within the first 4 weeks, you're almost at plateau, you almost reach what you can reach with the higher doses of the drug. This is UAS7 change over from baseline, coming from 30 going all the way down to well, single digits. So that's great. And now looking at the 2 components, the itch and the wheals, expected results in terms of -- they basically look the same. And why is that? Unlike other itchy diseases, let's take atopic dermatitis, for example. The inflammation and the itch in urticaria are super closely linked. Why? People with chronic urticaria are not itchy when they do not have wheals, not because of their disease. So it's the wheals that make them itchy. In other words, if you reduce the wheals, you will reduce the itch. Everything else would be unexpected. And you can see here, there's a very comparable reduction in the itch because there's a similar reduction in the wheals. Coming to the responder analysis, and we had some discussion yesterday on why is it a little bit different on the left and the right, let me run you through it. We looked at responders defined as UAS7 or 6 or less. What is that? That is when you look at the banding of the UAS7, minimal disease or well controlled. Some people say well controlled, I'd say minimal disease because it's a disease activity score, and you have a mild disease all the way up to 14. And then if you bring it down to 1 to 6 points in the UAS7, this is minimal disease. So that's a target that we want patients to reach. And you see that 2/3 of patients with the highest dose reach that target, minimal disease within 12 weeks. Phenomenal. Now if you're a purist like myself, treat the disease until it is gone means until it is gone, gone, gone, not minimal. So we want patients to have no more wheals, no more itch, no more angioedema. And this is why you take the UAS7 of 0. What does that mean? That means for 7 days in a row, you did not have 1 wheal or any itch. That's absolute. That's what we want to reach. That's the best we can reach. And you can see that for one of the doses, it's half of the patients who achieved this is in 12 weeks. Again, phenomenal. And I was asked before, "Well, why is it that the higher dose, the 300 milligrams every 8 weeks are not higher?" And I can't tell you, but I can tell you that this is probably due to the somewhat low numbers that we see here through the heterogeneity of the response, but take it that these are great results in terms of producing complete responders, and I predict that we haven't seen all that this drug can do in chronic spontaneous urticaria yet. But I also want to, at the end, point your attention to how patients who have failed omalizumab may benefit from this treatment. We use omalizumab in all patients, who are antihistamine resistant. And we see a variable response. Some patients respond and have a good response. Others do not respond. Now when it comes to being treated with this mast cell depleting approach, we see that there's no difference in patients who've never had omalizumab, in patients who have had it and in patients who failed it. And that makes complete sense because omalizumab goes against one very well-defined pathway of mast cell activation, Ig-driven engagement of IgE receptor and the activation of mast cells that then results in the wheals and the angioedema. But in patients who don't have this pathway or indirectly do not have autoimmune chronic spontaneous urticaria that also uses this pathway, omalizumab does not work. But this is not important to barzolvolimab because it is downstream of whatever pathway of activation of mast cell is relevant in individual patients. So it does work when oma fails. Yes, the safety, which I guess you have a couple of questions on, to me, is rather boring. I had seen safety results from the CIndU study where we've seen somewhat higher rates of whitening of hair and some impairment in taste, which we're able to reduce by reducing the dose. So here, we see that there are skin and tissue disorders that show up, but also in placebo, we see nervous system disorders that show up. Infection and infestations are similar across the group. I was somewhat surprised coming to this conference and being bombarded by questions on neutropenia. I did not expect that at all. Neutropenia is not an issue here. It was an issue at the very -- it wasn't an issue. It was a topic at the very beginning when we came with the first results in chronic inducible urticaria, where we saw that small dip, single dose small dip, and people were asking me, "But what happens when you do this again?" And I predicted that it would be the same that every time you come with barzolvolimab, you would see that small, irrelevant, clinically insignificant dip in neutrophils that would recover as the effects wane, and that's exactly what we see in this study. The signal that we obtained is not of clinical relevance and doesn't have me concerned. We do see hair color changes, which is interesting from a biological point of view. And if you heard what Tibor said about the non-human models, and this is also seen in mice, then it is interesting to see that the hair follicles melanocytes are affected, not the skin melanocytes in the epidermis, interesting. And discussing this with other hair experts and fans of hair follicle biology, the most likely explanation for this is that there is a cycling of hair follicle melanocytes that leaves them vulnerable at some point during that cycle, anagen, catagen, telogen cycle of hair follicle growth and cessation that does not occur in the epidermal melanocytes. So we don't see depigmentation of the skin. We see some whitening of hair in patients. And at one point, I'm going to show you pictures of this because sometimes I get the question, all of the hair goes white. No, it never all goes white. It's in more intense or more pronounced whitening of pre-grayed hair. That's the most common phenotype that we see. Occasionally, we see whitening or graying of hair. Where graying of hair usually does not occur, pubic hair, also sometimes vellus hair, which patients find peculiar but not a deterrent to the treatment. No one has ever stopped treatment because of this or because of taste changes, which we also observed in some people. Neutropenia, you can see here, low levels, transient, mild non-clinically relevant, happy to discuss further if you have questions on that. All right. So we are making good progress. We have 12 weeks that show us that it's a very effective treatment in chronic spontaneous urticaria across the 3 doses tested, most pronounced with 300 milligrams. And we're looking at the long-term data now as it emerges from the 52 weeks. We see that in more than half or half -- a little bit more than half of patients, we reached 0 disease activity, which is where we want to bring people, and that's very encouraging. We see a similar pattern of response in those patients who did and did not respond to omalizumab who did or did not have omalizumab in the past. We see a safe a safety profile that's very encouraging, tolerability that's very encouraging. So we're very happy to see this treatment option progress further, and we're looking forward to more results to come. Thank you for your attention.

I'm Allen Kaplan and the reason I'm here in part is because I've been involved in the study of both the pathogenesis and treatment of all types of urticaria since about 1970. And so what I'd like to tell you about, first, a little bit about the history of drug treatment of chronic spontaneous urticaria. If you go way back, we had 2 choices, antihistamines, which relieves it perhaps in 40%, 45% of patients because, as you know, does not stop in most patients, and a large percentage don't respond to it at all. And in those days, the alternative was steroids in fairly high dose. But the side effects, I won't go through with you, but they were legion. I had patients come in to me in wheelchairs, which is an extreme, but I'm a rheumatologist, so I used to treat arthritic diseases where being debilitated or coming in, in a wheelchair was common. I'm saying, "Oh, what happens in my practice? I'm practicing allergy today." And they had steroid myopathy to such a degree they were unable to walk. And besides hypertension and being disfigured in all the things of steroids, but that was it. In those 50 years, we had the antihistamine steroid. Xolair was a big step forward because it works in a lot of people, and that's a good side effect profile, but as you heard, it's not for everybody, and there's a heterogeneous response to it. But for sure, it was a big step forward. And the last drug was cyclosporine, which actually -- it's used preceded Xolair a year or 2 it's effective. But what we deal with there in terms of a side effect, especially if you go more than 6 months to a year of hypertension and a progressive decline in renal function. So the point at least in part that I'm trying to make is that having new drugs that work at urticaria has taken decades, a very long time. And they are not without side effects and ones much more severe, potentially than what you've heard about today. So now talking for a second about what makes a hive. As Marcus mentioned, there's the inducible urticarias like cold -- cholinergic, which is exercise when you begin to sweat, overeat, you break out in the hives, dermatographism where you scratch the skin and everywhere that you scratched, you break it. You wouldn't do it, you self-inflict and you would induce a hive. But what's interesting about those -- So those are acute and their quickie response. If you expose the cold sensor the person to the cold, the hive comes in a couple of minutes. And it's also fleeting, but it's recurrent each time with exposure. What's interesting there, when you study the science of it is that the mast cell is the key, and there's not much more of an immune response involved in it. If you do a biopsy, you don't see much. So it's more clinical that the inducer, a temperature change or sunlight for solar or being overheated sort of body temperature and sweating in cholinergic makes a mast cell degranulate, and that is the whole story. And barzo in the data thus far with it is close to 90% stopping that. And I'm not surprised because the focus there is not on -- just on the mast cell but almost exclusively so. Chronic spontaneous urticaria is very complicated. And -- but the mast cell being activated is fundamental to the underlying condition. But there are many immune mechanisms that are activating that mast cell and they are different in different patients. Further, there's a group of patients, no matter how long we've studied it in whom the immune mechanisms that we understand are not present. So there's much more work to be done. And what is endogenously activating those mass cells in some people has not understood at all. And in everybody is a complex mix of immunologic activation of those mast cells. Also bear in mind, it's endogenous. That's how we got the word spontaneous. The patient could go to bed feeling fine, do anything in particular, wake up the next morning and they're covered with hives and their lips are swollen. How did that happen? And for a long time, it was thought that there must be some unknown exogenous stimulus that is doing this. And of course, there is none. It's basically autoimmune so that it is an overactive immune system that is attacking the mast cell as a target in multiple ways. As Marcus mentioned, it's -- the mast cells in the skin, there are too many of them in many patients. So the numbers are up. They are primed -- I hate to use the word, it's almost like twitchy because we can do skin testing in a chronic urticaria patients with agents that we know will activate a mast cell in all of you. But if you do,a bunch of you, who I hope don't have hives and chronic urticaria patients, the wheal size in the urticaria patients is magnified because those cells are primed to be -- to activate and release their stuff. And so over this time, we have the antihistamines, Xolair, cyclosporin over 50 years. And now we have something that is a new approach that actually targets the underlying cell without which you cannot have a hive. So you saw the data thus far, and it's looking very good. It works irrespective of our ability to subtype patients. I mentioned that it's heterogeneous, and there are some groups that we can measure this or measure that. And we see little differences in the responsiveness to either Xolair or cyclosporin that we could perhaps predict, although not good enough to determine in an individual patient, which one you ought to use first. This drug hits it no matter what because you're hitting the mast cell irrespective of the stimulus that is activating it. So I think it is truly a novel approach to any kind of urticaria. And it will, beyond that, when you think about disease in general, any disorder that we have where mast cells may be a participant with other things and not just the focal point as it is in urticaria, this drug becomes very interesting in terms of what its effect might be. And you, of course, study it and you kind of work backwards because if it works, then you know the mast cell was involved, and there are many diseases in which its a suspect but not yet known. A word about the side effects. A funny thing is you all know, I'm not involved with the study, although I know all about it. And I'm working around minding my own business, and a lot of people approach me and they usually tell me about some difficult time patients. Would I comment on it. But some have come to ask about this drug, and it's interesting that a few of them asked me about the neutropenia, of all things. And so what do I know about the neutropenia? Well, you see a blip that comes down and that it's irrespective of the dose they used, then it flattens out as you watch it in the course. And although not shown, they have data that with time, it really comes back up, and it never reaches the levels where we were worried about infection. So the neutropenia is not really all that relevant to the discussion altogether. It's also known that if perchance you got an unusual one where it happened to be low enough that you would be worried about it, if you stop the drug, it comes right back. And the hair changes, I think Marcus discussed what is known. We know that, that too is completely reversible. And it's not like I'm going to turn black or when I had black hair it was going turn white, but it's streaking or a patch here and there. And in the study, though, when you think about side effect, it's still like 90% of patients didn't have it. You're talking about a small percentage of patients who had it. Well, if you think about what we dealt with for 30 years with steroid side effects, or cyclosporin side effects that we still deal with, I'm not worried about these kinds of side effects. Nothing is perfect. And this is a really good drug with great potential for efficacy, truly minimal side effects and broadly effective in urticaria, irrespective of the known heterogeneity of the disease. So we've not had anything quite like that and to see actually mast cells sort of dissipating in time within the skin, that's pretty unique. That's the kind of thing researchers dream about if they're interested in a disease like urticaria and angioedema. So I'll stop that. And of course, all of us will take questions on any aspect of this for -- from all of you. Thank you.

[Operator Instructions]

Yatin Suneja from Guggenheim. So 2 questions. So first, on the efficacy, and then we'll address the neutropenia. Could you put in perspective these data relative to what we are seeing from the new drug because there seem to be newer data coming out from the BTK inhibitor. So just curious to put these data in perspective how you are viewing those data and how you're going to be sort of using barzo once it gets to the market? And then the second is on the neutropenia, could you -- maybe for the company also, could you help us understand, did you see -- like what great did you see -- it seems like there was 1 discontinuation related to neutropenia. What happened to that patient? And then is that the patient that also had thrombocytopenia?

I can address the neutropenia question. We had -- in the study, we had 2 Grade 3 neutropenia. They were right below 1,000, Grade 3 is 500 to 1,000. One patient in the study discontinued due to neutropenia. That was a patient that dipped below 1,000. The next value was coming up and very close to 1,000. And the protocol, that patient had to be discontinued. That was a rule in the protocol. So that patient discontinued, their accounts recovered. Everything was fine. We had another -- the other Grade 3 patient on the next test was above 1,000. So they continued on, continued to receive doses and did fine. There was 1 patient listed discontinuing for thrombocytopenia and neutropenia. And the story with that one is that the patient developed thrombocytopenia during the study, but then we found out that the patient actually had a history of ITP. And so it wasn't evident before starting the study. So we discussed it, and we just didn't feel comfortable having a patient with ITP on the study, not knowing what was going to happen. So that patient went off. The investigator also described neutropenia in that patient, but in fact -- as an adverse event, but in fact, the patient's neutrophil count was normal. They had -- it had declined as it does, as you expect it to, but it did not reach any grade level, it was normal. So that's the story with that patient. And then I'll leave it to you guys for how to compare the efficacy.

Yes. Maybe just to say that there was no clinical relevance in any of the...

Yes, no infections due to neutropenia, really nothing. It's just -- it's an asymptomatic lab test.

BTK inhibitors are developed as a new treatment option for chronic spontaneous urticaria. So far, we have data from 3 of them, fenebrutinib, remibrutinib and rilzabrutinib. The fenebrutinib study showed clinical efficacy and liver signals that led to the discontinuation of this program. Remibrutinib completed Phase III and looks -- I'm going to make air quotes clean, by and large, although there were some minor signals on bleeding that will be followed up, but it didn't have the liver signals that we're seeing with fenebrutinib, neither did rilzabrutinib in a small study that we presented here at Quad AI for the first time. BTK inhibitors, even modern ones and much more selective ones like remibrutinib and rilzabrutinib compared to first generation or early BTK inhibitors come with a bit of baggage. So this is something that we will need to monitor as we go into long-term treatment with BTK inhibitors. This is something that we don't want patients to get pregnant on for sure because of the severe implications of BTK inhibition on the development of the immune system. This has impact on outcomes of vaccination. So there are a couple of situations where we need to be very aware that BTK inhibition, especially in the long run, needs close monitoring. On the plus side, and this is certainly welcomed by many patients, these are oral drugs. So that will be quite a change once we see these treatments coming to the routine clinical management. They're not really comparable, I'd say, because of the different MOAs that they come with when it comes to Barzolvolimab. The Barzolvolimab results that we shared in terms of safety and tolerability, they don't come from effects of Barzolvolimab on mast cells. All of these effects come from the effects of Barzolvolimab on non-mast cells, other cells that carry KIT. So that's one of the major differences -- and that's really all there is for Barzolvolimab. So that component of targeting KIT on non-mast cells, that's where that tolerability spectrum comes from, and that's not the case for BTK inhibitors.

You may be aware of this. But given the questions and seemingly concerned about the neutropenia. If you're on the 500, you're going to get in trouble. And if you be between 500 and 1,000, people are cautious and that was the Grade 3. And if you're over that, that approach 1,500, for sure, nothing is going to happen. So I'm 7,000 and if I were 1,500, I need you or I would know the difference. And that's the way it's going to be, in most folks who are taking this drug. So if you hit the outlier that happened to go lower, will then you stop it and do something else. And that's what we do with every drug that we have ever had. And [indiscernible] is interesting in that both of them have something to do with the mast cells. So everybody is thinking about that. Let's try to stop main cells one way or another. But the name of it, Bruton's tyrosine kinase and then -- it because it's the kinase in a hereditary disease. Bruton's agammaglobulinemia where you don't make the antibody and it's congenital and hereditary and have infections, and people worried about lowered it with a drug, you might get the infections that would resemble the hereditary disease. Well, fortunately, that has not happened and probably because it does not wipe out the enzyme, it just drops it down enough to help urticaria. So it's a very interesting drug. And it's the -- right now, perhaps the only other one other than Barzol that's targeting beta cells in one way or another that we're thinking about. But nothing depletes beta cells other than [indiscernible] drug, and that may have some unique features just across the board in terms of what the potential is for the future.

Sam Slutsky, LifeSci Capital. Two questions for me. I guess, first, when looking at the serum tryptase levels between every 8 week and every 4-week doses, was it fully suppressed during the entire dosing intervals? Or was there some bounce back between doses in some patients? And is that something excited for Phase III dosing? And then the second question is just on the nervous system disorders and skin and subcutaneous tissue disorders on safety. What did that entail?

So I can answer the first question regarding the PD analysis, which is still ongoing. So we're not reporting out specifics. What we can say is that we saw profound and very sustained tryptase reductions particularly at the higher doses that were consistent with what we've seen in the prior studies.

Yes. And I can -- so the skin and subcutaneous tissue disorders were mostly urticaria and hair color changes. So -- and the percentages of those are reflected below. The neurologic, the predominant things in that category were headache, and then taste changes were included in that. And taste changes occurred in about 4% of the Barzol-treated patients. So it didn't make the list of the top -- the most frequent AEs, but they did occur. And then the other things in that category, were just one-off sort of nonspecific things. We had dizziness and numbness and most thought to be nonrelated and mild.

Kristen Kluska, Cantor Fitzgerald. Congrats on these data. So on the Grade 3 Neutropenia, at the end of the day, this occurred in 1.3% of the patients in this trial. And can you give us a sense of how many patients you're seeing at baseline do present at that lower level of normal? And then from a commercial implication, I know you guys have been transparent in the past that if you're at that lower limit of normal in the beginning, you'd either need more monitoring or you may not be the best patient for this trial. But really, what I'm trying to get at is it's a very small percentage, but how would that play out commercially based on where these patients present at baseline?

Yes. So I think I don't have the exact number. I mean we have sort of a normal -- we required people to have normal blood counts to go into the study. And it's sort of a normal distribution of that. As you mentioned, we have seen a pattern. It's really quite a predictable decrease in neutrophil counts. So if you start low, you go lower. And so it's that's really what happens. So the people that tend to have gotten to Grade 3 tend to be at the lower range. So I don't know if that answered your question.

Maybe from a routine clinical physicians point of view, this is something that we look at in every patient anyway, no? There's a very small set of basic measures that the guideline recommends to do only four tests, and that is one of them. So we will have information that could have us react either by follow-up monitoring or whatever we do, but that information will be there. So it will not prompt additional investigation in patients that are not done anyway already.

Okay. I think that's an important point that these patients are already getting these measurements regardless, and it might only require additional follow-up should they be at that level. And I think a lot of people in general really just focus on this post-Xolair market opportunity. But as we've seen in your presentation and others, a majority of patients actually haven't tried it before. So can you give us a sense of the hindrance for trying Xolair. And then also just in general, why you think a lot of patients aren't responding? Do you think the true market opportunity is really post antihistamines or just post Xolair? And I know Novartis just put out a lot of big numbers about what they think about the market opportunity and how many patients they're treating with biologics.

So look, I don't see this as a post-Xolair treatment. I see this as a second line treatment in antihistamine-resistant patients. There is no head-to-head with Xolair as of now that would guide us, but the fact that it works in non-Xolair responders does not mean that, that's the patient population that is reserved for, on the contrary. Xolair is a good drug in those patients where it works. But it's a bit unpredictable at least in general practice also in resident derm and allergy practice as to who will respond and who will not. Who will be a fast responder or who will respond so slowly that it won't be good for them. And what that means is that there are reservations in the population for several reasons in physician populations to use Xolair that do not apply to Barzolvolimab, which is an all-comer treatment, which works in all patients irrespective of how their mast cells are activated. So this is where I see it as a viable second line treatment option. Certainly from a guideline development point of view, you would meet with Barzolvolimab of the criteria. It's been shown to be effective in this patient population. There is no head-to-head or major evidence to suggest that it is -- has a different safety profile than other second line treatment options, including Omalizumab. So this is where I see it as a drug.

Yes. And let me comment on that. Let's think backwards for a moment. There are patients who respond to none of the drugs that we are talking about. So that's a no-brainer. You would use Barzol in such a patient. We have cyclosporin that in the guidelines is used for Omalizumab failures. And you're dealing with blood test on a regularized basis and blood pressure checks, the drug works, but you could easily replace that in its position in the utility vis-a-vis guidelines. So the drug is surely good enough in terms of what we know about it in terms of efficacy to side effect profile to at least compete with Xolair in terms of therapy for this disease. So it would be like you would be thinking of it at least potentially second line, and it will compete -- but in terms of you were asking about some limitations. But here's one, when Xolair was originally came on the market, which, of course, was for asthma, right? And had a black box warning because of anaphylaxis. And it was 3% to 4% in asthmatics and it's still as close to that. It's closer to the lower figure. Well, that black [drug], that scared a lot of people because the warning is a certain percentage of people [anaphylac]. It happens that the proclivity to anaphylactic to have anaphylaxis is higher if you happen to be an asthmatic. And the incidents in chronic urticaria is lower, but that doesn't take the black box warning away. So our dermatologist friends, particularly in the United States, shy away from using Xolair. And many of our -- it's not a primary care drug per se, but they could, but they're reticent to it. It feels complicated to them, and then they have to deal with the side effect. And as I said, the dermatologists are not comfortable. They'll use all sorts of drugs like cyclosporine, which does other skin diseases, they're comfortable with. But Xolair, they're not. Because it's got that asterisks with anaphylaxis. So the allergists treated all the time, so we're not worried about it. So -- but that's a limiting thing and it limits even advertising on television. The fact that, that warning is there. So there are a number of reasons for why Xolair, which is probably the best thing we have now has not as a global use as we would wish it to be, after it. And then the next thing that we would wish would be new embedded drugs. So here is an opportunity.

Thomas Smith, Leerink Partners. Thanks for putting together this event and congrats on the data. First of all the company, can you just remind us how you define the Omalizumab-refractory patient subgroup in the study? And then for Dr. Bauer and Kaplan, can you help put these data specifically in context and talk about how meaningful that consistency of activity is across both the human-naive and experienced patients when thinking about some of the other treatments in development.

So the definition that we're using is that is patients who have received Omalizumab at a labeled dose and that they -- the reason they discontinued Omalizumab was either that they had an adequate control of symptoms or they had an adverse event that was related to Omalizumab so that's -- by their history, that's how we define it.

In relation to other drugs under development right now programs? Well, we talked about BTK inhibition already a little bit. I didn't talk about Dupilumab yet, which is licensed now in Japan for chronic spontaneous urticaria, very interesting. And on track to be licensed for CSU in the U.S., Brazil, and the EU. So this is certainly something that will come to the choice of treatments we can offer to patients who are antihistamine resistant. It's clearly different from Barzolvolimab in that it works as a sub-population of patients. There is some overlap in the responsiveness with those patients who respond to Omalizumab, although there are Omalizumab nonresponders who can respond to Dupilumab. I'd say on the plus side, dermatologists are very confident and very familiar with this drug already. There's a number of indications for which Dupilumab is licensed for, and it seems to be very, very safe. safe drug which is what we need in the long-term treatment. But again, in the hierarchy, when you think about it of doing things, blocking mast cell mediators, which is something that would apply to this drug as [indiscernible] 413 comes out of mast cells or axon mast cells or blocking individual pathways of mast cell activation and then taking out mast cells altogether by silencing or by depletion. The broader scope or the broader scope that right now is addressed by any program is with Barzolvolimab and mast cells depletion, so this is where this stands right now. There are some other interesting developments. We talked about Tezepelumab for the first time at this congress, which in a small study failed primary endpoint, but showed very interesting disease-modifying effects where if you stop the treatment, you have a long term versus long-term sustained treatment, which may become interesting as we develop drugs beyond mast cell depletion as we go deeper into the immunology or upstream of the mechanisms that lead to mast cell activation. Well, these are early days for Tezepelumab. And well, unfortunately, we cannot talk about mast cell silencing right now anymore, which was a program that was ongoing for quite some time, but Lirentelimab failed in CSU in the placebo-controlled study, although I hope that, that treatment approach per se as a concept will continue to be developed. But if you have any questions on a specific program or target or MOI, I'd be very happy to discuss.

Omalizumab hits IgE and has many consequences, right? Dupilumab its IL-4 and IL-13 simultaneously, which are needed to make IgE, right? So it's one step prior to that and affects at the same time to cellular infiltrate to a degree. And you all know that it's a terrific drug for atopic dermatitis. It sort of wonder drug for that when it came into being. But you could look at the data for yourself, it's different from [indiscernible], it's different from -- certainly Barzol. And we'll see about its position of where it would be if marketed in the United States. I would be confident about perhaps using it before cyclosporin for all the reasons that I told you, I would be a little bit less so as to where it might advance to look at the efficacy and see data yourselves and you can compare the various drugs and see for yourself. It's not quite the same. And theoretically, of course, targeting the mast cell is way out there, right? This is more distal to the action of where you want to be to try to stop a high, at least theoretically. So I was a bit surprised that -- I'm not surprised that it was effective in atopic dermatitis or asthma. The data are good and actually surprised me a bit because I didn't think it would work that well in urticaria because it's more distal -- so -- but it did. And it's being considered in the U.S. And I just heard about the Japan approval. I heard about is this morning as I was looking at. And -- but chronic spontaneous urticaria is a disease of high interest, and there's a lot of ideas out there. So you'll be comparing and discussing many different drugs. This is so far the most unique one.

Let me add some high-level info on prevalence, but also the need to treat and to develop better treatment options. We are grossly underestimating the prevalence of chronic spontaneous urticaria, that has many reasons. Most of the data that we base our current estimates on prevalence and incidents on are 30 years old and, therefore, come from studies that today would not be performed as such. And they don't account for any increase in chronic spontaneous urticaria that we may have seen over the past years, including new cases that emerge from the COVID pandemic. So we are underestimating the prevalence of CSU. I've seen people use 0.1 or 0.2 for the U.S. as an estimate, which is nonsense. When we look today with good approaches like we did in China just last year, we come out at 2.6%. So that's -- this is unexplainable. Even if there are geographic or genetic free disposition differences in terms of background. We have many more CSU patients than is currently calculated with to make these cases. And something that's very important for the development of chronic spontaneous urticaria drugs is that not only are we currently not doing a good job, you saw from these 80% of patients who have uncontrolled disease. But this comes also from not using the drugs we have in a way that they should be used. Today, 1 out of 10 patients who should be on Xolair is on Xolair. It's a nightmare. And 60% of patients who have this disease are not seeing a physician. And this is simply because people are not aware that there are new treatment options that we know a lot more than 10 years ago. And this is in part due to the silenced tumbleweed in this disease. No one talks about chronic spontaneous urticaria compared to similar prevalence diseases like psoriasis or asthma, where there's a lot of noise, a lot of drugs, a lot of players, a lot of interest, a lot of patient advocacy. Urticaria is silent. And that will change. That will change with every drug that will come to chronic spontaneous urticaria, we will bring more patients to treaters and more treaters to treat. And that's what I see for the next 10, 15 years.

Got it. That's super helpful. And just one question for the company. If you could just remind us in terms of next steps, timing for meeting with the FDA and what you're looking for out of a Phase III trial design?

So what we've guided is that we would look forward to initiating the Phase III studies during the summer. So you can imagine that at the end of Phase II meetings with the FDA are going to be done well before then. So -- but that's the guidance we'll give you.

And in terms of the Phase III, just what we've guided before is we anticipate having to have two placebo-controlled studies, where we have conservative estimate of 1,100 patients per study, and that's really based on the safety database that we need. We're hoping it will be less. We have to discuss where we're going to get all the patients from to fulfill our criteria, but it would be the -- I think the pathway for approval is well defined in terms of the endpoints that we're going to look at and so forth.

And once we nail down the timing and everything else, we'll certainly communicate that with the Street.

Great. Roger Song from Jefferies. So congrats for the data, and thank you for doctors' comment in the presentation. So a few quick questions from me. So one is understanding this Phase II is continue the dosing. So you will have 52-week 1 year treatment by the end of the year. So what would be the expectation for the safety and efficacy? Will we be seeing further improvement on the efficacy and the safety? Particularly in neutropenia, what should we see from there? And then in terms of the neutropenia, maybe just hopefully, it's the last question related to neutropenia. How likely the FDA will require CBC monitoring in the label? Will that be a concern or hurdle for community or the dermatologist to adopt Barzol for the treatment? Last question from maybe just like a summary, understanding majority of the patients or a large portion of the patient should be on Xolair but not on Xolair, Barzol potentially can be the option for them. So what will be the product profile, you really can convince those physicians to use Barzol as an option, particularly allergists and dermatologists that we know may be slightly different between practice?

So yes, I'll start. So the -- so I think the 52-week data, we need to have long-term safety data for the drug, which is why we designed the Phase II study that way. I think in terms of Neutropenia, what we've always said is we see this pattern where the counts go down in the first 4 weeks and then it stays the same and repeat dosing doesn't make it worse, and then it will come back up when the drug is off. And that's what we expect to see. So -- but we've shown it. We showed it in the Phase Ib, and we've shown it in this study so far. So that's what we expect to see. And then we're just going to be looking for just other side effects. Do any of the KIT- mediated side effects perhaps become more frequent? It does anything else show up, so it's really just reassuring ourselves about the long-term safety. In terms of the question about whether FDA is going to require monitoring, I think we really -- we have to see what the larger experience with the Phase III study is going to show. And again, what we see so far is this quite predictable decrease. Most people stay within the normal range. If you're lower in the range, you may get to lower values. But so far, no infections associated. So I think what FDA will be looking at is just what is the frequency of counts? And do you have any clinical consequences to those counts? And then that will be what will determine whether you need monitoring. It's really how monitoring is imposed. We think it will help the physicians manage the patients better. So I mean one scenario is the one Kristen mentioned where you -- everybody has to have a baseline CBC as Marcus reminded us in urticaria, and so if you know you have a low baseline, you might check something later, for example. But I think it's premature to speculate on what that would look like right now.

As far as guidance on efficacy, we haven't guided on efficacy, but what we saw in the Phase Ib is that we did see a deepening of response a little bit over time. So that's what we're hoping for. But certainly, the safety as well as can we get a little bit more of a deeper response going forward, that would be certainly a key to us.

There will be a great interest with a longer-term study to see if anything changes. But I would predict and I've advised the case on a net day thing, but I've never been on their panels. But they're going to be interesting is -- interested in, first and foremost, are you seeing any infections in these patients? And any dip beyond what is already seen. Otherwise, my best guess is that if it stays kind of the way it is they will not require monitoring. There might be -- they could at most have a lower level when you get the initial value where they say, "Okay, maybe you should have a value greater than some number, but it's going to be a low number just for safety concern. That's all I think would come of it. But most likely, most likely, they're not going to comment on it if there's no infection.

I think one of your last question was on implementation of clinical practice and how that would resonate with patients and physicians. And I think this is a very nice profile whereas an injectable, every 8-week injection is attractive compared to every 2 weeks or every 4 weeks right now. We know we can push intervals with oma in some patients to 5 and 6 weeks, but not to 8 weeks. That doesn't work in most patients. So that's unique for now. And I don't think that all patients will require 8-week dosing. I think many patients can go beyond that given on how long it takes for mast cells to return to baseline levels. And there's some room for improvement or, let's say, optimization of the use of the drug where if we achieve killing to an extent, mast cell killing to an extent where we have the clinical benefit, let's say, Allen and I discussed earlier, 85%, 90%, any guess is as good as that, you probably don't need 100%. But if you bring patients to that level, and that may, to some extent, depend on where they're coming from, do they have double the number of mast cells, triple the number of mast cells or normal numbers of mast cells. But if you achieve that, the maintenance of mast cells absence could very well be achieved with longer treatment intervals and/or lower doses, where I think it's absolutely feasible to speculate that 12-week dosing 4x a year is possible as we achieve the status of muscle absence and are looking to maintain that.

I, first of all, support that and agree with Marcus on that because the mast cell regeneration rate is the key to how you do that. And the way in the final analysis, the drug might be used is at a certain protocol until you achieve clinical benefit and a certain level of mast cell depletion, and then you may be able to extend the interval and achieve the same thing up to a point because it takes time for the mast cells to regenerate. And as we discussed, 85% and 90% is great. And if you don't want to raise questions, don't reach 100%, right? Because the next question is how do you live without mast cells? But I can tell you, you can live without IgE, and nothing happens to the people. That's the closest we come. So I think that's a futuristic thing, but I think it's probably correct and that may be the way the drug ends up being used after we study it a lot more.

Chris Jenner, Rocksprings Capital. Doctors, Kaplan Maurer, I'd be interested in kind of your projection of what the typical Phase III patient looks like? And what prompts the question is the most severely affected patient, you've commented on the use of cyclosporine or short-term corticosteroids. And Dr. Maurer, you really impressed upon me that this is a very significant unmet medical need and patients have a significant daily burden. So I'm wondering about the washout period and the randomization to placebo as to whether those patients would want to kind of take the risk to get into the study. Now on one hand, coming out of this meeting, there's going to be tremendous enthusiasm for these data. But anyway, I think you get the gestalt of the question, what does the Phase III typical patient look like in your mind given the necessity to have a washout period and try to isolate the sole effect of Barzol?

Marcus, take it first because you're doing it -- we're doing -- you might have a comment.

With washout you're referring to Xolair, right? With washout, you're referring to now Xolair-treated patients who come off and go into the study?

Or cyclosporin in [indiscernible] consort [indiscernible].

Yes. You're worried about rebound in the interim. Yes, sir. Okay.

Yes. Well, what I expect is that oma-naive and oma-experienced patients will be included, and oma-naive patients are plenty. Because we discussed only 1 of 10 patients who need Xolair should be on Xolair, is on Xolair -- so there are plenty of patients ready to go into these clinical trials in all of our countries. I do expect, and I would love to see some oma experience, including oma-failed patients. Now these are typically off oma already. So no one goes off oma to go into the clinical trial. This is not what happens. But they are around, they are around and are waiting for new treatment opportunities, including those offered by clinical trials. So doing CSU studies is not difficult. There may be different challenges because you're going into a patient population who in many countries -- well, in all countries is eligible for Xolair treatment. And in some countries, it's easier to get them on Xolair as compared to others. So imagine the situation, patient comes in failed [antihistamines] now maybe with the expectation to be prescribed Xolair in our center, and here I am offering participation in the clinical trial where placebo is an option. So this is the kind of situation that may be a challenge in countries where it's very easy to bring patients to Xolair, but it's still overcomeable, as we know from current Phase III trials. I expect patients to be very similar, high disease activity, high rate of angioedema, high rate of markers of autoimmune CSU, long duration of disease years. This has over the different Phase III studies that we've seen in the past 5 years been a consistent pattern.

And it's -- the patient distribution for the subsequent study is going to be similar to what has been in the past. And previously, that -- it's not that they didn't become symptomatic in some circumstance, especially antihistamine washout where you -- if we're having any efficacy, it rebounds right away and it comes back, but it hasn't stopped, and they hang in there. And as bad as it is, it's not a long way usually and then you start the actual study. On that point, you just reminded me just in terms of thinking about the disease coming back to -- if it's morbidity on the population, this is not addressing your question. But you should think of it, it has been likened to having in terms of disability, how it messes up people's lives, quality of life. It's akin to moderately severe Crohn's disease and Grade 3 heart failure, Grade 4 is a person who would have trouble walking across the room. So Grade 3 is 1 step beyond that, maybe being [indiscernible] with a 2-block walk. So the -- it just emphasizes the -- in people's minds, the way we underestimated, it's just a high but little itch -- and so far removed from reality. And it just reemphasizing the point that new agents, new mechanisms, new ideas and also having the disease, the awareness of the disease increasing all over. And first and foremost, physicians because if they don't know about it, they won't use it, and some of that starts at meetings like this. And the good news is, take a look at this meeting and see how many abstracts, posters, presentations and other things are focused on urticaria right now. And that's in part because of all the possible drugs that we have. So it is you in the pharmaceutical industry that drive that to a certain degree because I can tell you when it was no good treatment, there was no interest. You could be smart as you could be and work out molecular mechanism we there's interest in that, but it's a small cadre. You get a drug that works boy, and it goes way out of. And I think that we're going to see that, and continue to increase because good drugs and good ideas are out there and coming.

And as good as Xolair was, it didn't live up to the expectation in terms of making the noise around the disease that you would expect -- it was late in the game for Xolair. It was an established asthma drug. The budgets were low. It was life cycle handicapped, if you want. So we would...

Like to mention that black box -- that really has been painful in a sense because we know that it's the asthmatics that are proposed -- predisposed to having the anaphylaxis compared to the urticaria people, but it doesn't matter.

We are in the days where a little noise will make a lot of impact. And a big noise will make a huge impact. No mobilizing patients and physicians to bring patients to treatment. I have one more comment on the Phase III population, which is what I would hope to see, and that is to be a bit more open as to the comorbidities we allow. Our clinical trials suffer from being very restrictive in an exclusion criteria on making the patient population as healthy as possible except for the disease of interest, which is not good to begin with, although I understand the reasons for it. But here, we have a unique opportunity that Allen highlighted twice, that is we will find out with Barzolvolimab what other diseases are mast cell driven. And the fact that we now have a rival program, clinical rival program for Barzolvolimab comes from an observation and equals one, but we saw that it is true moving forward, of a chronic urticaria patient being treated with the drug and losing not only the chronic urticaria but also the [indiscernible]. Let's make use of that. Would I be surprised if at one point in time, one of my study patients came back at me and said, "By the way, my migraine has stopped. By the way, my gut problems are a lot better." But we can only see that when we include these patients, right? So right now there's a long list in all Phase III trials of what you cannot have when you go into a Phase III trial. So let's look at that really hard and make sure that it is -- there's a good reason to exclude patients with other diseases, not only to make them as, I'd say, similar to the real world population as possible. But with that specific question, what other diseases can benefit from us or depletion?

Would you mind if we do after [indiscernible]

Patience is not one of my strongholds. I mean, we'll figure it out for sure, right, because it will happen in real life. But unless there's a really super good reason to exclude someone with a migraine, why would you? Unless there's a really good reason to exclude some of the endometriosis or [indiscernible] or you name it, there's a bucket list of 50, 70, 180 diseases where there's a mast cell signature. Let's be innovative. See who can go in and who shouldn't.

Here's a specific one. The synovium, the lining of our joints in rheumatoid arthritis is loaded with advanced cells. And everybody talks about all the other cells, T cells, B cells, activated macrophages in the complement system, but there are loads of beta cells in rheumatoid arthritis in the synovium. Who knows what would happen if you really, really wipe those out.

We will be surprised in 10 years many diseases are mast cell-driven, mast cell-dependent or at least must mast cell co-immediate. Yes.

Jana from TD Cowen. I just wanted to ask a quick follow-up on safety questions. So specifically for the neurological kind of headache, taste changes as well as for neutropenia, can you specify where -- like which doses those occurred and whether they were the 150 mg dose or the 300 mg dose?

Yes. So for the -- yes, so for the neutropenia, the 2 -- the Grade 3s, one was at 75. The one that discontinued the study was at 75 milligrams. And I don't recall, but we haven't really seen a dose response in terms of the Neutropenia. So it's pretty consistent across all the doses, I can say. And the other question was the...

For the neurological.

The neurologic findings, actually, the taste changes we saw in we saw 1 in 75, 1 in 150 and I believe the rest were in the 300. So we saw it at all doses. And the other -- we had headaches, we saw it at all the doses, and nothing else particularly stood out.

And then just an unrelated follow-up. I know that there are other drugs in development that are also targeting kind of [indiscernible] depletion. And you said that you are -- Barzolvolimab is differentiated based on the fact that it targets dimerization rather than blocking the ligand. This is obviously borne out by your data. But why mechanistically do you think that blocking dimerization is actually going to be more potent than SEF directly?

I don't think we -- we're claiming higher potency. What we're claiming is just being a different mechanism of action. And data that you get from Barzolvolimab is not data that you can transpose onto other KIT inhibitor antibodies. So clearly, there will be some overlap with other antibodies that kind of starved mast cells from stem cell factor. But we do believe that this unique mechanism may offer different properties. And we've seen that. If you look at some of the preclinical data reported on other KIT inhibitors.

[indiscernible] cancer. Can you just comment on the [headaches] concerned?

Yes. In fact, I just look they're mild, mild headaches. It's a great one.

[indiscernible] on the day transition then indication for those patients. All right, start over, Sam Slutsky, LifeSci Capital. On the headaches, was it transient the mild ones? And then for patients with infections, do they stay on study after cleared with typical treatment, et cetera? Just any color around that?

Yes. Yes, the headaches were mild and transient. And the people stayed on study after the infections, and the infections that we saw were really just the whole variety of run-of-the-mill infections that you see. So we saw nasopharyngitis, influenza. We saw some COVID. It was really a mixture of things, but definitely patients stayed on the study after those.

Dr. Maurer, during your presentation, you said that you predict we haven't seen all that this drug can do in CSU yet. What do you mean by that?

Thank you. We have a mast cell depleting drug that works by getting rid of mast cells. How sure are we that in this study, we got rid of all the mast cells? And I'm saying that because from the CIndU study, we know that we got a good solid depletion. On average, we saw a 90% reduction in mast cells. At one point in time, many patients did not have mast cells for a couple of weeks before they came back. And we thought it would be sufficient to monitor tryptase levels here in CSU to extrapolate on depletion of mast cells. But we don't have the mast cell counts. My prediction is that because we go into patients with variable levels of mast cell numbers in the skin, we did not deplete mast cells in all patients to the extent we would see that complete response. There are patients here who did not show complete response. Remember that the UAS7 equal 0 graph where we have 50% or 49% of patients who did not quite achieve that? That's short of what we did in cold urticaria, where we are sure that we depleted all of the mast cells in all of the patients. So I would love to see how the effects of muscle depletion or the doses of a mast cell depleting drug like Barzolvolimab relate to the baseline situation of having mast cells. I think this is where we still have room to help patients with high mast cell numbers who need higher, at least preliminary or initial doses, to kill all the mast cell populations. I think people will be very similar in terms of what they need to maintain absence of mast cells, but I think they could differ in how much killing dose they need at the beginning in order to get rid of all the mast cells. So that's certainly an option to increase the responder rates and the effect size in these patients. The other thing that I need to -- we talked about this, we need to think about is how long does it really take for mast cells to come back and to be ready to start all of this again. And we looked at the relapse of mast cell numbers and in CIndU patients, but because we right now do not have that information for chronic spontaneous urticaria, I think we are to profile mast cells numbers in the skin as we deplete them and as they come back, to educate optimized treatment regimen in terms of dosing and intervals to maximize on the drop. That's what I meant by there's room or opportunity to improve on the outcome.

Do we have any additional questions? I'll turn it over to Anthony to close.

Great. Well, I want to thank Dr. Kaplan and Dr. Maurer for joining us this morning and being so gracious with their time. We really appreciate it. Obviously, we thank you all for attending this morning and those that are on the webcast. And we certainly look forward to presenting more exciting data this year, both on this program and CIndU, and looking forward to speaking to you during the year. So have a good day.