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

Hi. Good afternoon, everybody. Thank you for joining us for our barzol Phase Ib multi-ascending dose CSU update study results that were presented this morning at a poster here at Quad AI. And just to give you a format of the meeting, I'm going to ask Diane Young, our Chief Medical Officer, to come up and to discuss the results of the study. And then we'll ask Dr. Maurer to come up and make some comments. Dr. Maurer has a prior obligation and he needs to be out of here by 5:00. So I just want to be cognizant of his time there as well. And I also want to thank the people that are joining us today by the webcast. Having said that, we're going to make some communication of some forward-looking statements today. So I ask you guys to refer to our SEC documents, which discusses our forward-looking statements, our risks and everything in those documents. So with that, as I said, the agenda is going to be the Phase Ib study. Dr. Maurer here is with us and here to answer some questions at the end of the day. We also have on the table in front here with us is Dr. Tibor Keler who is Co-Founder and Chief Scientific Officer of the company as well as Diane who is our Senior VP and Chief Medical Officer. And with that, I'll ask Diane to go through the data.

Thanks, Anthony. I'm very happy to be here today. And I just want to start off by introducing Dr. Maurer who really needs no introduction. We're so happy he's able to join us today. So he's the Professor of Dermatology and Allergy and Head of Dermatological Allergology at Charité University in Berlin. And he also coordinates the global allergy networks of urticaria and angioedema reference and centers of excellence. He is deeply committed to the study of urticaria both in the clinic and in the laboratory, and he has participated in more than 60 clinical trials, including the Phase Ib and Phase II trials from Celldex. So we look forward to your perspective after going over the data. So I'm really happy to summarize the results from the Phase Ib multiple ascending dose of barzolvolimab in CSU patients, which were presented earlier today. In the study, we saw a rapid, profound and durable symptom improvement in patients with moderate to severe CSU refractory to antihistamines, including in patients with prior oma experience, and we observed clinical activity in multiple dose cohorts. Barzolvolimab was well tolerated with a favorable safety profile, showing consistent results with what we've seen in our previous single-dose studies. We believe that barzolvolimab's unique mechanism of action as a mast cell depleting agent has broad potential in mast cell-driven diseases. And we believe that these data support our ongoing Phase II studies in chronic inducible urticaria and CSU. And we announced today that we are expecting to complete enrollment in the Phase II CSU study by the end of third quarter and report top line data in late fourth quarter or first quarter 2024. So as Dr. Maurer will much more eloquently describe, chronic spontaneous urticaria is a disease which is driven by mast cells. It's extremely debilitating disease which impacts all aspects of the patient's life. It is currently treated with antihistamines and omalizumab is the only approved biologic for the 50% who don't respond to antihistamines. So there is a great need for new therapies. So this is the study design. You're all familiar, I believe, with the design. It's a multiple ascending dose study looking at 4 dose regimens and placebo, and all doses were given intravenously in this study. So patients received either 3 doses of 0.5 or 1.5 milligram per kilogram, given 4 weeks apart, or 3 or 4.5 milligram per kilogram given 8 weeks apart. And then they were followed out to 24 weeks. The primary objective of the study was safety, and the primary end point for clinical activity was the main change in Urticaria Activity Score 7 at 12 weeks. We presented interim results from this study at EAACI last year. And at that time, we presented data out to 12 weeks for the 2 lowest cohorts and data out to 8 weeks for the 3 milligram per kilogram cohort. So for this poster and at the time of the data cutoff, all 3 lower dose cohorts had completed 24 weeks and all patients in the 4.5 milligram per kilogram cohort were through the 12-week treatment period. But we were able to show data out to 20 weeks for this cohort because, at that point, data from 6 of 9 patients was available, so we thought that was enough to begin to look at the results. So these are the demographics and baseline characteristics. The patient population had moderate to severe chronic spontaneous urticaria with UAS7 around 30 and UCT around 3, which indicates poorly controlled disease. Patients had had CSU for a long time in this study, more than 5 years, on average. All patients were refractory to antihistamines, and 37% of the barzolvolimab-treated patients had prior omalizumab. The majority of these patients had an inadequate response to omalizumab, which was defined as patients who had persistent symptoms despite omalizumab and patients who were intolerant of omalizumab. And we'll talk more about that later. So this is the activity shown by Urticaria Activity Score 7. This was the primary activity measure in the study and the barzolvolimab-treated patients had rapid and durable improvements in Urticaria Activity Score 7, with the most profound and durable effects being seen at the 3 highest dose groups. We know from the tryptase data that these are doses at which KIT receptor appears to be saturated. And as a reminder, the 1.5 and 3 milligram per kilogram doses given intravenously correspond to the 150-milligram and 300-milligram doses that we are giving subcutaneously in our Phase II studies. Another notable thing about this data is how long the symptom improvement lasted in these 3 highest dose groups. Patients still had reductions even at 24 weeks, which is 16 weeks after the last treatment that they received. This shows the ISS7 and the HSS7, which are the 2 components that make up the Urticaria Activity Score 7, specifically for itch and hives. And you can see a similar pattern of rapid and durable improvement when looking at these 2 components. Now the most important thing to patients is really complete relief of symptoms, which is Urticaria Activity Score 7 equals to 0 or a complete response. So the majority of patients treated at doses greater than or equal to 1.5 milligrams per kilogram achieved complete response by week 12. It's 57% for the 1.5 milligram per kilogram group, 44% for the 3 milligram per kilogram group and 67% for the 4.5 milligram per kilogram group. And to provide context, omalizumab has a complete response rate of 36% in their prescribing information. And once again, the duration of complete responses is very impressive. So 7 of 8 patients who had been treated with barzolvolimab at 1.5 milligram per kilogram or 3 milligram per kilogram, and had a complete response at week 12, maintained their complete response through the 24 weeks. So another measure of activity is the Urticaria Control Test, which really measures symptoms and how well the disease is controlled and the patient's general quality of life, and looks back at 4 weeks, the previous 4 weeks. And UCT is validated for both CSU and CIndU. And with this, UCT greater than or equal to 12 is considered well-controlled disease, and UCT equal to 16 is considered complete control. On the left, we see the mean change in UCT scores over time. And on the right, we see the percent of patients who achieved UCT greater than or equal to 12 over time. More than 60% of patients achieved well-controlled disease by 12 weeks which again persisted through the follow-up period. And it was interesting to us that patients in this study started with a lower UCT than in our previous CIndU study, but the magnitude of increase in UCT was roughly similar. So that was kind of interesting. So this chart shows the pooled results from the 3 highest dose groups comparing omalizumab naïve patients, shown in black, to omalizumab experienced patients, shown in orange, looking at UAS7 on the left and UCT on the right. And this is a really nice way of showing that the pattern of response is really identical between the oma naïve and the oma experienced patients. Now 19 patients in the study had prior treatment with omalizumab, and 11 of the 19 were considered oma refractory, which I gave the definition before. Most of them had symptoms despite being on an adequate trial of omalizumab. And of this patient population that we're looking, which is the pooled group of 1.5, 3.0 and 4.5, there were 5 of these that were oma refractory, and 4 out of 5 had complete responses by UAS7. So really, the oma refractory, again, subsets of patients, but we're having responses similar to the oma naïve and to the oma experienced, in general. So this shows the pharmacokinetics and serum tryptase. And consistent with our previous studies, tryptase suppression paralleled symptom improvement, and this demonstrates the impact of mast cell depletion on CSU disease activity. And tryptase has really been a remarkable biomarker for the program. It just is consistent from study to study. This is looking at the safety. So barzolvolimab administered with multiple intravenous infusions was well tolerated. Most adverse events were mild or moderate and resolved while on study. The most common adverse events for hair color changes, COVID-19, headache and neutropenia. And COVID in urinary tract infections were all considered unrelated to barzolvolimab. This shows the hematology parameters. And these are really consistent with what we have seen across our studies. We have not seen a pattern of further decrease of hematologic parameters with multiple doses. We saw transient asymptomatic neutrophil decreases as adverse events for 5 patients. Four of these were previously reported in the EAACI presentation. The new patient had an isolated value between 1,000 and 1,500 cells, which was above 1,500 on the next determination. So we're very excited about these data. We believe that the magnitude and durability of symptom improvement and the observed safety profile support our ongoing Phase II studies of barzol in CSU and CIndU. This slide shows the design of the Phase II study in CSU. The study has been ongoing since June. And as I said before, we now expect to complete accrual in this study by the end of third quarter and report top line data late 2023 or first quarter 2024, and we are all really looking forward to that. So now I would like to turn this over to Dr. Maurer to provide his perspective on the study results, and then we will open it up to your questions.

Thank you very much. Look, we're very happy with these outcomes. Obviously, this is the best we've ever done in chronic spontaneous urticaria when it comes to the treatment. It's a disease that really is devastating and underestimated in its impact. And to see what barzolvolimab can do in this patient population, which was a severe chronic spontaneous urticaria population, including patients who failed the only second-line treatment, is remarkable and gives us a lot of hope that we'll be able to do a lot better once we have this in our hands. There's a couple of things here that are very interesting that I want to highlight. Clearly, the dose response and the difference also between what we see in CSU and CIndU, I think that deserves some comments. Let me touch on the first one first. So we've seen across the 3 doses some variability. This is not unusual for chronic spontaneous urticaria. It's a much more fluctuating disease than, for example, CIndU, but to see that one time point you have something that's a little bit out of the curve is not unusual. That's to be expected. And to see the dose response, especially between the lowest dose and the 3 higher doses, gave us new insight on what barzolvolimab really does. We continue to believe that this is a mast cell depleter and this is why it works so well. But you have to answer the question why do you see this effect, the blue line. Remember, the blue line that goes whoop, whoop, whoop, and we actually call it the whoop effect. And that term was coined when we first looked at the low dose response to omalizumab where patients who were on 4-week treatment intervals, right before the next injection, the last week, wasn't so good. So they also went whoop, whoop, whoop and had that pattern. Now barzol is not oma, by no way. We are looking at a very different MOA. We see that primary MOA as in mast cell depletion. But what's going on in the low dose? And how can we interpret that? And my interpretation, I may be wrong, more data may be needed, are needed, is that, at a low dose, barzol doesn't kill the mast cells. But it still impacts mast cells. And from a therapeutic point of view, that's not so remarkable. But from a biological point of view, that is really remarkable because it shows us that KIT is such an important receptor that beyond keeping mast cells alive, it also regulates their activity. And because this happens early on, it may be something that contributes even at higher doses where you would assume that why wouldn't it happen at a higher dose when it happens at a lower dose, may contribute to this very fast onset of action that we see so this I find from a mast cell biologist point of view, very interesting, and KIT biology is poorly understood, and barzol will clearly help us to understand this better. Maybe from a clinical and patient point of view, the comparison between CIndU and CSU is important. We know that many patients have both. And this is another interesting and important point because we know that patients with CSU who also have CIndU can have different treatment responses to treatments other than barzolvolimab. So in the future, for sure, we'll look at patients who have 2 or more chronic inducible urticarias. Now the CIndU data to you may appear as black and white, and it is. This rate of complete response is unrivaled. We can't do better than 100% complete response, right, we all agree on that. And we do get a complete response in 100% of the high dose CSU patients, as I predicted. I told you so. No, just kidding. But it wasn't as clear in CSU as it was in CIndU. Why? Because we're dealing with a disease that is not as clear-cut and monolinear as CIndU. CIndU, you have the trigger. The trigger annoys the mast cells. The mast cells degranulate. It causes the signs and symptoms. The wheels come, the wheels stop and you're back to square one. You don't have a chronic inflammatory response and increased susceptibility of the tissue to respond to the next trigger. The next trigger needs to be exactly the same strength in order to produce a signal. And this is very different in chronic spontaneous urticaria. We're starting to see infiltrates that you do not see in CIndU. You do not see a lot of eosinophils, neutrophils, T cells move to the wheels in CIndU. But you do in chronic spontaneous urticaria. And what this does is it contributes to the wheel that is emerging, but they linger. Eosinophils can be seen in non-lesional skin in chronic spontaneous urticaria, which is post-lesional or pre-lesional skin. So in other words, what mast cells do in CSU results in effects that are different than in CIndU, and that could have made it more difficult to treat chronic spontaneous urticaria. And to some extent, you see that. We see complete response to a lower dose of barzolvolimab in CIndU. We half the dose, and we still see 100% complete response. But we need the higher doses in CSU, at least when we look at the first 24 weeks, to get to that complete response rate that we know from the CIndU. Do I think that we need these high doses moving forward? I'm speculating here, off script, this is just my thought on this. I don't think so because, once we've done the job of reducing these mast cell numbers, which tend to be higher than in CIndU, which tend to have downstream effects that need to normalize before we come to a normal skin as we have it in CIndU when there's no lesion, that, that may be a hit in the beginning and it needs some time for things to normalize. And then all you need to do, just like in CIndU these mast cells gone. So it will be interesting to figure out. And this is not the job for the Phase II. This is not something that we now have to solve. But it could very well be that by looking closer at the response to the treatment over time, we may have a dynamic treatment in these patients. And of course, we all think about how can we make this drug even safer, how can we improve the tolerability of the drug just like we've done for CIndU where we can have, by halving the dose, the rate of side effects and maintain complete response. I think there's still room for this in chronic spontaneous urticaria for now. I'm very happy to say and see that what we thought before we started the study is true chronic spontaneous urticaria is a mast cell-dependent disease. It is critical, critically dependent on mast cells. And when you take them out, CSU stops. And so this is really proof of concept that was necessary, needed, not unexpected and clinically, very, very meaningful for patients who struggle with this devastating disease.

Thank you, Dr. Maurer. We appreciate your thoughts on the subject matter. So as promised, we're opening it up for questions, realizing that Dr. Maurer needs to be done here by 5:00. So fire away. Kris?

Kristen Kluska, Cantor Fitzgerald. Congrats on the new data you've shown today at Quad AI. Would you say that the omalizumab current data is consistent when separating those who are refractory versus those who had some level of response? And how about amongst the different doses?

Anyone?

I can start. Yes, so I think because of the way we enrolled the study, we really can't distinguish among doses because it's just a few patients in each dose. That's why I lumped those doses together. But I think that clearly, the trend in those omalizumab refractory patients is with a high response rate as with the total population. And Dr. Maurer can probably talk about why that's such an important thing.

Yes. I mean, of course, it's important when you only have 2 treatment options and you show that another treatment works in patients who failed both of them, that's a big relief moving forward because now we know that we can do better than omalizumab. I'd be cautious though because the fact that barzol works in oma nonresponders, which is clear from these data, argues that it's a more overarching mechanism where you don't need to block individual pathways of mast cell activation. It just doesn't matter to barzol how these mast cells were activated. It just knocks them out and that does the job. But when you look at the way we did the study, then you have to acknowledge that there is not as rigorous assessment of the response to omalizumab, previous response to omalizumab, as you would do if this were like assessed prospectively. So in the future, what can we do? We can go against oma, no fear here, that would settle that once and for all. Or we could really include patients where we have UCT data, UAS data on the previous omalizumab experience. And that includes patients because that happens today, patients who receive higher than standard doses of omalizumab. I think this is something that we should explore moving forward so that we can be even more confident that this is what happens. But for now, I think what's fair to say is that barzol works where oma doesn't, and that's about as much color as we have on the topic.

With 24-week data on hand now, how do these findings set your expectations for the ongoing Phase II trial? And can you detail some further advantages you see with things like exposure and other factors now that you're using subcu?

Yes. Okay, we can speculate. I love to speculate. It's nice. So I believe that the subcu dose will work as well as the IV. I think also that the rate of -- well, there will be no infusion reactions, not that there were many in the IV. But that's a clear benefit. Patients like that. And we'll make it fit-for-use, self-administration. That's the ultimate goal. And that's what will happen. This is how we will move forward. So there's a clear benefit in moving to subcu. Other than that, it's early days. We've just started with this study, so we'll see how it works out. I can tell you that in the long run, we'll be interested in long-term data, both on can we maintain that clinical response, can we steer patients through difficult times which may come in terms of trigger exposure. Only when you go, let's say, for 52 weeks will you have that fall period where viral infections tend to happen; or will you have that aspirin that patients take, although they shouldn't. And these triggers that we know from daily life make patients have exacerbations. And that's why we're very interested in the long-term data. But the longer we treat, the more often we treat, the more confident we become that this is really something that we will continue to see moving forward. I remember the discussions that we had when we only had single-dose treatment, what will happen to this, will it get worse if we treat; things that we talked about, will that get worse as we move forward. And I said then I don't think so, and it didn't get worse by treating longer. And so yes, we need those safety data moving forward, and we will get a longer exposure with the trials that are ongoing. But in the long run, we will need treatment that we can give for many years in these patients before they lose the disease by themselves.

Evan Taddeo from Guggenheim. I have 2 questions. First on dosing maintenance phase. I'm interested to hear your thinking about maintenance dosing. Would you think patients will be taking barzol every other month? Or is there an opportunity for patients to take fewer doses over the course of the year?

Yes, it's a great question. Given what we know today, I don't think that you need to give it every 4 weeks. When you kill a mast cell, you really need to make sure it's dead, then it will stay gone. In other words, I think of barzol as we shoot them, and that's it. And then they need to bring new precursors back to make new mast cells, to become mature, to become reactive again. We don't need to keep hitting the system when there are no mast cells yet. And I think that's true benefit because patients, when you think about it, are happy to inject every 8 weeks rather than every 4 weeks, probably happier to inject every 12 weeks than every 8 weeks. So I think this is a true benefit that the mechanism of action of this approach rides on mast cell biology. We know that the skin mast cells that drive the disease that they are, well, very expensive to make for the host. So it takes a long time before we see these precursors come into the skin, start to mature and then become reactive. And we have to understand that a little bit better because right now, we have on the relapse data only matching muscle data for the CIndU study. But it looks like we have weeks and weeks and weeks, if not months, of absence or low levels of mast cells that will not allow for signs and symptoms to occur. And of course, there's huge benefit. Can we push the envelope? Can we bring these patients to 12-week interval of injections? And I do believe it's possible. So short answer is we will be able to treat less often than every 4 weeks, I predict.

Got it. And the second question is so it looks like in the 3 mg/kg, there were 2 late responders. So I'm just interested to know what's going on there from an efficacy perspective?

Very good question. I don't know, but I'll be happy to speculate.

He's speculating. We don't.

Yes. I love to speculate. Look, we know that some patients with chronic spontaneous urticaria have increased mast cell numbers. We don't know what that means, and it's not consistent across studies or across patients. But the fact that it is possible, that it has been shown that individual patients have double, if not triple, the number of mast cells in the skin, means you're going against double, if not triple, the number of enemies. And that could be something that requires longer exposure or repeated exposure in order to get them down. Whereas in CIndU, it's very predictable. They have as many mast cells as we do always. That's not the case in CSU. That's a simple explanation that is testable, and I'd love to see if it's true.

Tom Smith, SVB Securities. Just wondering if you can provide a little additional color on the news of rescue therapy, and the study talked about differences between placebo and others.

Diane, in fact, if you could repeat the question. I'm having trouble with the audio on the Q&A.

So the question is if we can talk rescue medications on the study, particularly in the placebo group. So we have a lot of data from the study on rescue medications in terms of antihistamine rescue medications, which we have to analyze in more detail. But one of the things that we looked at was we just -- we looked through all the things that they had gotten. And there is a patient in the placebo group that got omalizumab and steroids. And they actually should have gone off the study, but they stayed on the study, and they had a response. So that actually affects the placebo curve in the study. So that's the biggest issue that we've identified so rescue meds. But we will be looking at rescue med data. It's quite complicated because the patients take antihistamines on it, they have to be taking them, and then they take them for rescue. And so you really have to do a very careful analysis. And with a small number of patients, it might be hard to see the whole pattern, but we're going to look at that.

In general, this is a minor point of concern, if at all. Rescue medication never affected the trial to the extent that you would have another outcome without it. We tend to overestimate the contamination by rescue medication, but we have to understand that these are short-acting antihistamines that are only taken on the day when they are needed. So there's little wash-over and patients are instructed to take the rescue medication when the symptoms get so worse at they're unbearable. In other words, they will document their disease activity as high on that day that they take their rescue medication. They will take it. They will have 6 hours, 8 hours of relief. Next day is a new day. So even though they take the rescue medication, it will not have contaminated the daily score or the wash-over score for the score of the next day. It really seems like we're adding treatment to them but not in the way we assess the disease activity the way we do.

Sam Slutsky, LifeSci Capital. Congrats on the data. A couple for me. So just to build on Evan's point, in the data presented, it looks like efficacy continues to go down over time. Given the kinetics of mast cell depletion, greater number in CSU, and then the removal of these other immune cells that get attracted, is there a potential for efficacy to keep improving as we go out?

I mean that's what we're going to try to find with even longer chronic treatment. I mean it definitely is going up during the 12 weeks. I don't if you have any.

Let me speculate. Look, you're probably going into a system with the increased mast cell numbers, other inflammatory markers that you need to normalize before you come to where you are in CIndU from the get-go. So the idea that you keep treating these patients, which is what we will do, is treating these patients when they're at a different point. When you treat the second time, you already have less mast cells as when you treated the first time. So I think the idea that the response will continue to improve, or that you may even have longer intervals or lower doses needed to maintain that response, is something very attractive and could be explored. I think it would then be explained by changing the baseline and reducing, by those first hits, the systemic inflammation that is there which you no longer have once you do it a second, third, fourth time.

And then for Celldex management, just on the receptor saturation, remind me what that looks like between the 1.5, 3 and 4.5 mg/kg group and then the translation of that into the subcu doses being used.

Yes. With regards to saturation, we've seen that those dose levels lead to the same level of stem cell factor accumulation in the blood. And that indicates to us that we've had hit a similar level of saturation, whether it's the 1.5 that's given every 4 weeks or the 3 milligram or the 4.5 milligram. So I think, as we've discussed in many occasions, we think once you're at saturation, it's really more about the length of exposure you get from that particular dose, and that's how we would expect to be able to think about regimens that are perhaps given less frequently. Subcutaneously, we've shown in our healthy volunteer study that the 300-milligram flat dose gave very similar pharmacokinetic profile and tryptase reduction profiles as seen with the 3 milligram per kilogram IV formulation and similarly for the 150 compared to 1.5. So our expectation is, with the different regimens we have in our subcu Phase II study, we're also hitting saturation for the majority of patients, either with the 4-week 150 dose regimen or the 300 every 8 week.

And just lastly, real quick, on the placebo patients who got rescue omalizumab and responded, was that a complete response they had? Or what kind of response?

Yes, they had a complete response.

That was very transient complete response, and they were antihistamine refractory. So they're never exposed to oma.

Tom Smith at SVB Securities. Could you just provide or maybe comment on the immunogenicity that you're seeing in the study to date, and I guess your expectations as you move to the subcu form?

Right. So we have seen some ADA to the antibody given in the IV as we've reported here. We're really pleased to see that it's had absolutely no impact on the exposure levels. So the pharmacokinetics, even at the lowest doses, are actually even better than what we had expected based on single-dose treatment. And this is perhaps because we've removed the sink, the target, and the subsequent doses are really lasting a long time. So we have yet to address the longer-term question about ADA response, particularly with the subcu dosing. I think we'll be able to answer that question with the Phase II studies. But so far, the ADA that we've seen is certainly not impacted pharmacokinetics or clinical activity.

Okay. Great. Yes, I appreciate that color. And then maybe one for Dr. Maurer. If I could just ask you to maybe contextualize the omalizumab experienced patients in this study versus some of the other contemporary Phase II or Phase III studies for other agents like remibrutinib or dupilumab?

Yes. I'd rather not because we have not a lot of information on the oma experienced of these different patient populations in the different trials. Sometimes they're called oma experienced. Sometimes they're called oma failures. And that is again because this is a retrospective look at the patients who went into the trial. Sometimes chart data is available, sometimes physician global assessment of what that previous omalizumab experienced was like without details on how long have they had oma, what other medications did they have, what was the dose, what was the actual response, was this a partial response, was it a complete nonresponse, was it a mix between did not tolerate and didn't respond well enough. So this time, I don't speculate because there's just not enough data to say that based on these different oma experienced populations, including oma failures, we conclude that there's a difference in the follow-up treatment in these Phase II studies and Phase III studies now, yes. I mean like you said, it goes for dupi, it goes for remi, it goes for barzol. And I think we need more information on these patients as they go into the trial or a true head-to-head or prospective assessment of their oma experienced to really be able to compare different treatments for their effects in these oma experienced populations.

I have a question coming in from Kambiz Yazdi with Jefferies who wants to know if there is a dose-dependent drop in neutrophils observed and what the differences were in the baseline neutrophil levels in the treatment groups.

So for the 3 doses that we call the saturating doses, very similar change in neutrophils, but the 4.5 milligram per kilogram group had a slightly lower baseline than the others. So it looks lower on the chart. But if you look at the baseline, it's a bit lower than the others.

Any other questions in the room?

For Dr. Maurer, could you just discuss all the places where barzol's profile could fit? I know it's still early days. But as you think about antihistamine refractory, post-Xolair, post-dupi, kind of how it could play in each of those roles.

Sure, Sam. I think that barzol will work in all diseases where mast cells contribute to the pathogenesis. And that's a long, long list. But you have to differentiate between diseases that are critically mast cell-driven. And now we know that chronic urticaria across all the different types of urticaria and phenotypes is such a mast cell-driven disease. The other 2 diseases that we really need to look at, and we're in the process of wrapping our head around this because they are mast cell-dependent, mast cell critically dependent diseases, mast cell cytosis and MCAS, holding huge potential, from my point of view. Now these diseases must respond, must, because we wouldn't have these diseases as humans if we have no mast cells. That's the smallest part of where barzol -- in terms of numbers, that's a really low number in terms of patients overall who could benefit from barzolvolimab. The next tier is diseases where we know that mast cells play a role. We're not sure how important they are, but we think that they are very important. These include all the Type 1 allergies and Type 2 inflammatory diseases from anaphylaxis to food allergy, to asthma, to allergic rhinitis, to chronic sinusitis with nasal polyps, to all of these IgE Type 2 inflammatory diseases where mast cells are known to be increased, be activated. There is a correlation between mast cell activation and disease activity. So very strong circumstantial evidence that mast cells contribute to the disease. And here, you may see some diseases where 60% or 80% of patients, depending on their endotype, will be complete responders just like in chronic urticaria. And the other 2, 20%, may not be complete responders, maybe partial responders, because they have a different endotype. I'm thinking asthma here where we clearly know that there are different endotypes where the role of mast cells in terms of contributing to the pathogenesis may be different between different populations with the same disease. And then there are other diseases where we can have fun speculating. And you and I, we talked about the long list of diseases that are out there. I'd say that bullous pemphigoid, we just mentioned, must respond. I think that rheumatoid arthritis must respond. I think that the chronic inflammatory intestinal diseases will respond; IBD and Crohn's. Mast cells are professional troublemakers when it comes to inflammation. So any chronic inflammatory disease, you have to at least be ready to see that kicking mast cells out will improve it. The caveat is that mast cells can be bystanders. I haven't seen a single yet where they're only bystanders, where they're not in some kind of feedback loop, add to the trouble that's there. But it is possible. It is theoretically possible that in a disease where you see increased numbers of mast cells, maybe even increased rates of mast cell degranulation, when you knock them out, it will change nothing about the clinical profile. But it's highly unlikely. And if I had to guess how many diseases will respond to oma, it's somewhere between 30 and 75. It's that high. And that's a huge population with varying degrees, obviously, but that's where it gets really interesting because we will not only be able to help patients who we currently can't help, but we will also learn about where mast cells play a role and then, further down the road, how they do it. And that's where the scientific merits of this approach are. Great.

Evan from Guggenheim again. Two more questions. First, now that you've narrowed guidance for the Phase II CSU study, where does CIndU fall relative to CSU?

Yes, one at a time, Evan. So we're guiding on the CSU. We have a better handle on that. We think CIndU will be sometime in '24, but we'll probably give an update on that midyear. We'll have a better handle on that since it started a little bit later.

Got it. And then one more for me. In terms of EoE, Dr. Maurer, you mentioned there are numerous diseases where mast cells are playing a role...

EoE is in there. I'll group that in there.

Exactly.

I forgot chronic prurigo. That's a sure bet. Chronic prurigo will work. So there's just too many. But if the guidance is whenever you see IgE be a driver, because IgE does that through mast cells, that's one argument. But there's other diseases outside of these classic Type 2 inflammatory conditions and IgE-driven diseases. And EoE, there's still a little bit of need to better understand the pathogenesis and the differential role of eosinophils versus mast cells. But look, eosinophils are not born in the esophagus or the skin or the gut or the airways. They are blood cells. And someone needs to tell them where to go, and no one does it better than mast cells. Now if you know a mast cell just hard and long enough, they will call eosinophils because they think you're a parasite. And they will want to fight you together. And they are buddies in crime when it comes to the disease. It's just like they're Batman and Robin when it comes to fighting parasites. So they are an effector unit where the mast cells love to call them for help when they can't do the job alone. And that's why I think it's a good target. Mast cells are a good target for EoE. And down the road, we will figure out just how many patients and how well they will respond from mast cell depletion.

Got it. Then with that context, where are you in preparation for the EoE study?

Yes. So we're still guiding first half of the year, and that's when we plan on starting the study.

Tom Smith, SVB. Maybe just kind of following up on that, now that you've laid out sort of time lines for the Phase II CSU timing, if we kind of play that forward, how quickly do we think we could turn around into a potentially registrational study? And what are the current thoughts around whether or not you would want to or need to go head-to-head versus oma?

Do you want to talk about the head-to-head?

Well, so head-to-head, so for regulatory purposes, we don't think that we would have to go head-to-head. We may have to do it for other reasons, in some way, because of pricing and things like that. But as far as starting Phase III, we're certainly going to plan as quickly as we can and get it started.

It will definitely be in 2024, Tom. The exact month, I can't tell you at this point, but it will be in 2024.

Any other questions? Okay, Anthony, I'll turn it over to you to close.

Okay. Well, thank you, everybody, for joining us. And Dr. Maurer, thank you for joining us. I know you've been extremely busy. And we thank you for your comments and your speculations, as you like to say. And everybody here joining us in person, I appreciate you guys coming, for your time. And as well for those that joined us on the webcast today, we appreciate you guys taking your Sunday afternoon and listening to our presentation. So with that, we look forward to updating everybody going forward. I'm sure we'll have conversations with all our investors, and we'll keep everything up to date. So thank you.