Chronic Spontaneous Urticaria: New Trials, Hot Treatments, and Patient Pearls with Dr. Jason Hawkes

[music] Welcome to Derms on Drugs and Video Podcast brought to you by Scholars in Medicine, the best educational platform of dermatology and provided in no cost to medical providers. Derms on Drugs is where cutting edge derm meets your dermis comedy. I'm Matt Zeyers and each week I'm joined by my residency buddies, Dr. Laura Farris in Tim Patton where we use our 60 years of combined derm experience to discuss, debate, and dissect the hottest topics in dermatology. It is everything you need to know to be on the cutting edge of derm and you'll actually have some fun listening. New episodes drop every Friday on Scholars in Medicine, Apple Podcasts, Spotify, and all the other major podcasts, platforms. Just a note for everybody, there is a video component, it says the key figures and tables and our beautiful faces on it. So I know most people listen in the car and just I got to tell you, I myself listen to 2x all the time, but if you want to see what we're talking about or see the articles or get the links to the articles, go to the Scholars in Medicine platform. All right, so this week we've got a great deep dive for you. This is going to be fascinating. We're going to what's a really hot topic in the world of dermatology, chronic spontaneous urticaria, and kind of the new drugs that we've got either available or about to be available. So let's just get right into it, Dr. Patton, what do you got? All right, my deep dive was in the March 2025 issue, diagnostics titled autoimmune thyroid diseases and chronic spontaneous urticaria, the role of hormones, anti-thyroid antibodies and ultrasound by pollution at all. This was a combined retrospective, prospective study performed at a university hospital in Serbia and I think if I tried to pronounce it, I would offend any Serbians who may be listening. Like Matt said, as a review of sorts, CSU is in the news, it's a hot topic. So just quick reviews, European guidelines for CSU published in 2022. Recommend a CBC and a CRP and/or ESR in all patients. And then they say, yes, total IgE and IgE anti-TPO antibodies for patients that are in, quote, specialist care. I don't know what that means. Are we specialists? I don't know. I don't know if US groups have officially published recommendations in 2014, recommended work up there, CBC, differentially SRCRP, liver enzyme, TSH measurement. Although there was a more recent New England Journal medicine article, chronic urticaria published 2022, that said laboratory testing in CSU isn't necessary and quote, maybe omitted. And that's what I do. I'll admit it. I'll practice. Wait, I'm with you, Patton. I generally don't order any labs on these people. I've got less something weird is going on. Ferris, you order any labs on CSU patients? No, totally based on review systems. Yep. Not one that I need to hand it over to. All right, Patton, go ahead. But, right, practice varies. I work with residents. And when we have a CSU patient, they'll say, should we just do the urticaria work up? I'm like, I don't know what that is. Yeah. We should do the urticaria work up to work with the work. Order that. And then, the study was conducted from 2022 to 2024 authors looked at different thyroid testing that was done on patients diagnosed with CSU and compared these results to 50 control patients. So they did have a control comparison over the time period of the study. There were 43 CSU patients table two reviews the clinical characteristics of CSU patients compared to controls. More CSU patients have allergies and infections with HPI lower a candidysis, other comorbidities. Oh, blah, blah, get to it. We need to check thyroid studies or not. No, I mean, they're, they're often abnormal. So figure one, the graph that reviews the thyroid testing studies. So compared to control CSU patients, statistically significant differences in TSH, T3, antithyroglobulin, and antithyroid peroxidase antibodies, no significant difference in T4 levels. Altruz sound thyroid abnormalities like lodgles, heterogeneous structure, more common in patients with CSU. And autoimmune thyroid disease, which I guess was based on ultrasound features. They didn't really go into that. It was more common in patients with CSU compared to controls. So this paper, you know, confirms what other studies have shown. There appears to be a relationship between CSU and thyroid autoimmunity. But, you know, everything you read, it doesn't impact therapy or change anything. I think on a review of systems, if you suspect thyroid issues, it would make sense to check it. But I am not routinely ordering any of these because clearly you're going to see abnormalities. I mean, the thyroid ultrasound, like that's not an horrible idea, right? A terrible idea. Yeah. Yeah. You know why they have more thyroid abnormalities because they get thyroid ultrasounds. That's it. Yeah. So, uh, so no, we see a lot ordering these tests. I'm still going to do what I'm going to do. I am going to do review systems, probably poorly, because I will say I definitely totally missed Graves disease in a patient. She had CSU. And then two weeks later, she called me. She said, does graves have anything to do with CSU? I was like, uh, maybe. And she said she went to her PCP and was having symptoms. And so maybe I did not do as good review systems as I should have. Uh, but yeah, routinely, I'm not ordering these. Uh, I don't know about you guys. So see, I think of TSH and T3 and T4 and the anti thyroid anybody. Is this like so easy? And when I look at this article, like half of CSU people had abnormal results. Am I, you know, I'm going to tell them, I don't think it's going to affect your CSU, but maybe you should go see an endocrinologist and see. If you, you know, should be on some thyroid medicine and then maybe you'll just feel better in general. But, uh, you know, I don't know. Yeah, I, I, I have had other patients where that's all they have are the, the, the antibody, like the anti TPO antibodies are the thyberglobulin antibodies. And endocrin doesn't, they're like, their TSH is normal. We're not, this isn't anything we would manage. I mean, I think most mainstream endocrinologists. But you, you, I'll be interested to see what Dr. Hawks are, guess is going to have to say. So maybe just a TSH. Did it, did it look at women versus men, by the way? Oh, probably, but I didn't write that down. So I don't know. I think most of the patients overall, the higher percentage were females. Like really? Yeah, that's what we expect. All right. So main takeaway to me, thyroid abnormalities were more common, but it may not mean anything. It's weird because it's, it's sort of in the guidelines. Like I think most people will be like, well, I am a specialist. The European guidelines say answer the order the anti-IG TPO. Like then what are you going to do with it? You don't do anything with it. It gets patients freaked out. I think there's some data that would suggest that the patients who have those auto antibodies are more likely to have refractory treat disease treatment. That seems to be consistently true. Like the big one is low, IGE high anti-IG TPO. That ratio, when that ratio gets really high, those patients tend to be more refractory to both anti-histamines and onalismab. But not that you wouldn't try it at least. Maybe with these newer drugs, maybe it'll be like, hey, if this is the case, then this drug will work better. But it's so early on in that. Yeah, we just haven't had all these options. What will be great is if there's a predictive lab that says, these are the people who should go on, the drug, where is these guys? If you're IGE, how are you going to do better on onalismab? If it's low, you're going to do better on, do picks that. If we just have more data to correlate, it would be great. But we don't have it right now. Well, that's kind of like what we're going to be talking about in next week's episode, where we may have a test like that with psoriasis. But let's get on to our next article, Dr. Ferris, where you got? So I have from the New England Journal of Medicine, Remi Brutanib and Chronic Spontaneous, Urticaria, Martin, Metz, et al. So this is a nice paper. It has one of these nice graphic summaries if you like to like see what is what was this in one page with pictures. I love those. So we can put a link to that in there. But this is these are two identical multi center double blind randomized placebo controlled studies called remix one and remix two that evaluated the efficacy and safety of Remi Brutanib and patients with CSU. Who had failed treatment with second generation H1 and a histamines. So patients were randomized to one to either get oral Remi Brutanib 25 milligrams twice a day or placebo. And the primary endpoint they used was the change from baseline to week 12 and the UAS seven score. What is the UAS seven score? It's the Urticaria activity score during a seven day period. So it basically it's a severity score for itch and urticaria hives during the week. So it's summing the daily scores for hives and itch into with the score of 0 to 3 over seven days. So it's kind of like the Pazzy for hives and the score ranges from 0 to 42 with higher scores indicating greater severity. Okay, so what is this drug? Remi Brutanib inhibits BTK which is Brutan's tyrosine kinase. It's a cytoplasmic kinase of the tech kinase family. And since CSU BTK is activated downstream of the high affinity. IGE receptor and mast cells and Bayes of Phills and it is responsible for histamine release, other pro and flammatory mediators and it is also probably responsible for BTK plays enroll and B cell activation so driving that auto antibody production by B cell. So maybe those patients who have auto antibodies maybe that's a little hint that BTK inhibitors might be an option for them but that's totally non-databased. Okay, so these patients had to be symptomatic for at least you know six weeks and had to have failed their non-sedating antihistamine and then they could be randomized. They also had to have for severity a UAS score of at least 16 with an itch severity over seven days of six and they also had to have a high severity score over seven days of six as well. They so they're about 300 patients per you know 300 patients in each study got Remy Brutonib. The average reduction in the UAS score was about 20 points in the Remy group and about 13 groups in the placebo group. So at week 12 significantly more patients, about twice as many in the Remy Brutonib group versus placebo had a UAS of six or lower so that's sort of a clinically significant result and if you look at how many patients had a UAS of zero which is no activity it was about 31 38 to 31 percent of patients on Remy Brutonib versus about six to 10 percent of patients on placebo. So these were you know statistically significant results. What about safety? This was actually like impressively safe. So the one adverse event that is reported with this is Patekiae. So moderate levels of Patekiae 3.8 percent in the Remy Brutonib arm versus 0.3 percent and the placebo arm was transient resulted in one patient did discontinue the drug because of it but not associated like platelet abnormalities or anything. So you know what do I take for this? I went and I looked and I was like how does this work relative to like Omelizamab or I won't say to pill you max I'm not going to steal your thunder mat but our oral antihistamines. So you know if you look at in the Remy Brutonib you know study on average the UAS 7 decreased by like 20 ish. For Omelizamab that number is also right around 20. If you're like well how about in placebo so what's the gap? The placebo reduction rate was actually a little lower in the Omelizamab studies. It was about 6 to 8 versus 13 11 to 13 in the Remy studies. So technically that gaps maybe a little better in the Omelizamab arm. We can talk about it when you talk about the pill you ma. For oral antihistamines we have a reduction of the score if you look across studies of like 12 to 14 but we don't really have like a placebo control rate. So you know I think this is interesting the safety is good I'm hoping there'll be like no lab monitoring with this. We'll see when it gets approved I'm curious if Dr. Hawks has any insight on to that but excited to have this as another tool. My other pearl every time I work with residents I'm always amazed that they don't know this but you know first line treatment for CSU is not sedating oral antihistamines at the dose of four times the labelled over the counter dose people they're like what do you mean you're going to give them four a day and like that is the first treatment. I'm the Lisa and the law often people don't know that so if you take the second line pearl on that is to be very clear that they have to take the non that not the D so you don't want to do like redeeming or clariting you're in yeah but yes that's I actually usually do four times the labelled dose of either clariting or allegor in the morning and then usually I'll do 20 milligrams of dessert tech at night if the patient wants right if I'm trying to like because I do think you start to get some sedation as you push the dose of the of dessert tech yeah but yeah either I'll sleep through the follow-ups with the internal which I was reading this study where yeah they said before going to amalism adverse cyclosporine like in and this controversial because it's not in the guidelines but there was a study that said if you introduce a four times the recommended dose of a second antihistamine a decent percentages of those patients like didn't have to go on to other therapy I mean that's a massive amount of antihistamines but I thought that was interesting so where's the air tech a day and four clariting a day yeah yeah uh uh uh uh uh uh uh uh uh uh uh uh uh uh uh uh uh uh uh uh uh uh I also thought the interesting thing with this paper was prior amalism ab exposure especially as it relates to dipilliamab right so uh uh uh 30% of the patients and both of the trials had prior amalism ab exposure I don't know if they teased out the effectiveness of amalism ab exposure versus non-amalism ab exposure yeah yeah I did not in this paper and the results they could have been hidden somewhere in a um supplemental material that I missed but it wasn't in the main body but yeah that is also interesting they did not exclude those patients important when you think about like some of the results of the dipilliamab CSU you know study the differ with Dupy I'm sorry with um amalism ab failure so yeah patent just before I forget send me that article about the giving people more because I always think of it as if if four x there's like a plateau effect yeah where if you're at four x and it's not working like five x six x ten x is totally safe but it's not going to help yeah adding I didn't know there was no article out there that looked at adding four times the dose of the second agent I will send it to both of you yeah yeah okay all right let's go into my spots as well let's go out to my study uh so this was dipilliamab in chronic chronic flotinia serocaryal liberty CSU Cupid to randomized double-wifed sleep control trials so they did Cupid A which was all there naive and Cupid B which is Zolaire intolerant or inadequate responders uh and then the big thing right the the sort of elephant in the room here so due to covid and slow enrollment for some reason they peeked ahead of time and looked to see how people were doing it's called an interim analysis and when you do an interim analysis apparently that reduces statistical power because what we're going to see is it number one it looks like the dupe just did not work as so in Cupid B who was Zolaire inadequate responders the dupe just didn't seem to work as well now there's some like well maybe it was just the statistic it was close and to be statistical significant on the whatever but they had dupe had to end that I'm having to do a third trial because the second trial uh didn't didn't hit his primary endpoint uh but that's one of the kind of excuses but whenever you look at the data it does look like it just doesn't work as well and only as map failures uh now so the in the studies had to have CSU diagnosed for longer than six six months yet have a or to carry activity score of 16 or higher you had to have an itch score of eight or higher in the week before starting people were on an a histamines and stayed on their their background stable in a histamines but they could increase uh their dose if they needed to for rescue uh if they were already on the max dose of four times they could get systemic steroids as rescue and if you got rescued you were considered a non-responder in the US the itch score was the primary outcome and that was the FDA said it had to be and then in the EU the early carry activity score was the primary outcome that's what they said it had to be uh now before we look at the right talk about the results one of the things that was interesting is that the ige levels decreased by 40 to 60 percent over time in both studies uh but the big takeaway that from this so do be works uh and people start to get relief especially from their itch pretty quickly but it's not a comparative trial but just the the overall numbers look very similar to remy brutinib in terms of how many how much people get better and how many people get better to the point where i i'm not confident saying one drug is better or worse than the other i think that right now as far as the data goes and say they're about the same and overall efficacy but remy looks like it gets there a lot faster uh is the takeaway and so it kind of feels like it's going to be you know okay do you want to drug this a new mechanism of action like where we looks completely safe but it's still new or do you want you know tried and true do be's been around forever uh that works probably just as well but just that maybe takes a little bit longer to get there the other thing that was interesting uh they didn't see any conjunctivitis so remains the case that atopic dermatitis is really the only disease that conjunctivitis seems to be an issue with dupe seems to be the same in terms of arthrauges and nuanced psoriasis that kind of stuff seems to be specific date. topic term was those things really weren't seen in these trials, but you know, relatively small numbers of patients so hard to know. Did you guys have any comments on it before we bring Dr. Hawks in? Now let's see. Let's get Jason the way in. I know he's an expert on this. It'll be fun to discuss the two studies with him. So first just for anybody who doesn't know him, you should, uh, there are Jason Hawks out there somewhere on the West Coast where all those wackos are, uh, but I don't know if he's I don't actually mean that, but the outdoor in the West Coast and I think of Dr. Hawks as the Urdicaria expert in the world of dermatology these days, Dr. Hawks, great to have you on the show. Yeah, thanks for having me. No, we're not we're not weirdos here. So we're a West Coast best coast, man. All right. So Jason, let's, let's just kind of get into it. So the first let's start where we started with Dr. Patton when, when you see a new Urdicaria patient, what do you, what's your workup? You know, what do you do any workup? You know, the three of us are now really doing labs. Um, like maybe we should do thyroid. What do you do? Yeah. So it's a good question. And I'm listening to the conversation. I think there's maybe a little cleanup we can do because I think there's some misunderstanding. It's important to make sure we're talking about the patients that truly have CSU, right? So differentiation from acute versus chronic, we're greater than six weeks. Those are our chronic patients. 80% of our patients have CSU, spontaneous by definition, right? No external triggers, not pressure induced, not heat induced. That's send to 20% of the chronic cases where there's a clear trigger. But if you look at chronic Urdicaria as a group, sometimes we'll call it C U. There's a lot of it. What's that? Let me interrupt you there. Because CINDO is one of those things that I'm always like, who cares? Like other than telling you like, don't get cold. Don't scratch yourself. Like do we manage them any differently? Yes. Well, so that interesting point, I think one, the part of what we're trying to identify is that we're trying to help patients not be miserable, right? So if, if truly there's an exposure that they can minimize, right? Then that's helpful. But to your point, you can't just be in a bubble and not get pressure. So if you have symptomatic dermatographia, like you kids can't stop having pressure. But, but I think like, I'll tell you to the point here. So the reason I got into Urdicaria was a second year medical student. I was diagnosed with cold Urdicaria. Actually saw one of the dermatologist's allergists and actually tried, they tried to enroll me in the homolizumab studies. But I failed the ice cube test. So even though it's clear that cold was the trigger and to the same way, I can't avoid cold. And I've had that so more than 15 years now. But, but I know that it's sort of anticipating that trigger that I can minimize disease. So like fine, going skiing or working out in a cold area, like that's something that I can kind of prep for. Sometimes it's taken more anti histamine. So, but I do think having knowledge of that trigger, I think is important. But I think I almost don't want to know because once I know that it's pressure to carry your dermatophys and record her to carry, if I document that in the chart, now I can't get homolizumab. I can't get Zola or Dupy or Remi when it comes out. I feel like it's almost bad for the patient to document it in the chart. You could probably say there's an overlap, right? I think they've even shown that, especially with their biographism. Isn't there a fair amount of patients? It's about 30%. And I think to your point, like we do a lot of things clinically that help us get to the therapies for our patients. And that's not going to change. We've been doing that for years and a lot of inflammatory diseases. But I think when we see these patients, what we're separating out is that we're, it helps patients to know there's not a cause per se, like an external environmental cause. What we're really saying in CSU and this gets back to you, what do we do for work up? Is that there's a, it's a not coincidental that twice the number of women get chronic or to carry it, right? They also tend to have a higher rate of autoimmune. So if you look at the two very specific mechanisms in or to carry it, there's IGE dependent mechanisms and IGE independent mechanisms. There's clear auto antibodies as one of the key triggers for activation of the mast cell. So even though checking thyroid and those things don't really change our management that are early carrier, what we're really saying to patients is that early carrier often precedes most of the comorbidities. So autoimmune thyroiditis is by far the most common. We see celiac disease, we see lupus, we see rheumatoid arthritis. So you know, we just had this in one of our trial patients that has subclinical thyroid disease. Once in the clinical trial, it wouldn't have passed our review of systems, but then in the trials like we check out a labs has, you know, fluorid thyroid disease, right? So we pick this up sometime. So I think what we're really saying to patients is that it's not going to change our management. But you're at risk because of the mechanism of forming auto antibodies that can hit other tissues that you just need to be aware of that. So as things pop up, I think Louis Loura that talks about the review of systems, it's good to say like, you know, if you're starting to develop some new things, I keep that in the back of your mind that you have this, you know, predisposition for autoimmunity, which strongly correlates with the early carrier, but it also correlates with other disease states. So I look at that way. So I don't tend to check lab, the early carrier guidelines. There was a huge debate about this. We just did the international order carrier guidelines revision in Berlin in December. And I'll tell you, even that group was split because Durham really felt like, is it really going to change much? And I think the overall recommendation of those guidelines was that we recommend against extensive testing. And I think that it's really recognizing some of the small, small percentage, about 1% of patients with chronic red carrier actually go on to find that there's some underlying malignancy or some other condition which can sort of drive activation of mass cells, but, you know, we're not going to look for those little ones. I tend to not do it. Let's give you the money. So in somebody with a negative review of systems, I had your feel fine. They're not getting fevers and I can join eggs. They're not, you know, do you do so normal review systems? Do you do any labs? No. I don't. Okay. Fair enough. I just have the conversation. Yeah. I agree. Yeah. I think we should have been invited to Germany. Why would we not think? No. I don't quite understand this. Where are we? We've been to Germany together. So, yeah, we have been to Germany together, not to make it our palace, but we have. For sure. So, I think, yeah, I think bottom line for the listeners is that we want to let those patients know that the labs are really to screen and make sure their health is otherwise good. And they just need to know that over time, there's a very high rate of auto-min conditions that develop in these patients, not directly related to the early care, but in conjunction with their overall risk. So Jason, how do you tell people that they don't need allergy testing? Right? Because that's the big, oh, food. What food? I need to see what can. What is the hard conversation? You know, honestly, it's these patients when they come in, we don't see a lot of, you know, I've had her to care for four weeks or six weeks. Like, we get those occasionally, but most of the time it's that I've been to, you know, a bunch of primary care doctors and the ER and, you know, I've seen an allergist or a couple of allergists or, you know, someone's psyched me through a bunch of these different treatments. And so, most of the patients we see are already in that well into the chronic face. And the fact is if they could have controlled their disease with cutting out milk or bread or, you know, they would have already done that. So I usually kind of started to say, look, if this were a simple fit, you probably would have already done it because you've cycled through, you've changed all your bed sheets, you've fumigated your house and, you know, you've done all this stuff already. And I think that's a good indication when we say that's why the definition of this disease is chronic spontaneous, er, de carry or what we used to say, you guys all remember the chronic idiopathic er, de carry, right? We're trying to highlight the fact that I like idiopathic better. I did, I did too. And I, and I, I sort of bring that up to say we're really differentiating it from the inducible, right? So this is internal, it's your native immune response, not that different from other inflammatory conditions. Nobody with rheumatoid arthritis sits around and says, hey, what food caused my rheumatoid arthritis? And they just start to get into mind that thinking about the immune system is driving their disease. And then you move away from that. So I say, what do you want the allergist to check? Because we know this your immune system, like, it's overactive, it's otherwise healthy. So I just try to break through that barrier conceptually. And then I try to quickly focus to, do you want to just, do you want to go through all that testing? And maybe if we can find an allergist because that's part of the problem sometimes, or do you want to just focus on getting better? Because I can help you there. And usually that kind of breaks that conversation. All right, I'm going to tell you guys how I do it. Here's what I say to them when they bring up food. I say, so do you know anybody who has like peanut allergy or shellfish allergy? Oh, yeah, my kid, my kid, my kid's school, blah, blah, blah. So when they eat the peanut, it's like two days later than they get some hives, right? Like, no, they, well, it's not. - Exactly, if there was a food you were allergic to, your mouth would swell up the second that you ate it. The fact that if there are no foods that your mouth is getting itchy whenever you ate it, we know it's our food allergy. And that has been the most effective like, okay. And then really emphasizing that we know it's autoimmune, right? - Yeah, and actually to your point, Matt, I say something kind of similar. I say, you know, have you ever had episodes of hives repeatedly where you didn't eat milk or bread or whatever they think it is? And that's a nice screening because the definition of spontaneous disease, they should be breaking out in the absence of what they think is their trigger. And so it's very easy for someone to say, like, I think it's this, cut it out for a week. The transit nature of urdie care, you're either gonna get it or not get it. And most of the time, if someone could say, well, I don't always get it with milk or bread or whatever they think it is, boom, that's it. There you go. So you took away your disease. This is a disease that cycles through, you know, very quickly in hours in most patients that it doesn't take you very long to tease that out. So that helps them conceptually kind of break that connection. - All right, so let's get into the drugs. So we're gonna kind of skip talking about Zollair 'cause the use in Durham is just, you know, there are some Durham's who use it. They don't need to learn anything new about it if they're already using it. The Durham's who don't use it aren't gonna start using it. So let's kind of skip Zollair. How do you differentiate them, right? So let's assume Remy's about to get approved later this year and let's say that that all happens. How will you, how do you differentiate them? - Yeah, I mean, two very different approaches, right? So we're talking about an injection, well known to Durham, you know, tried and true safety profile. We're then comparing that to an oral medication. So 25 milligrams twice daily, very fast onset of action. There are ones a little easier to wrap your head around in terms of how it works. The other is a little more indirect. So if we think about Remy Brutonib, right? B.T. K. inhibitor, this is the intracellular pathway within mass cells. So, you know, analogous to say the Jack stat pathway where it's intracellular, it's a kinase pathway, but it's going to be the, I think of it as a convergent pathway. So the IgE dependent and the IgE independent mechanisms go through B.T. K. So theoretically by blocking B.T. K, we should be able to also capture those patients who don't just have IgE mediated disease. So I think of it in that way where you're going to capture the type one autoimmunity, which is the IgE dependent first of the type to be autoimmunity, which is non-IGE dependent. So mechanism like IgE. I want to talk about that just a tiny bit more. Yeah. So the IgE dependent mechanisms for CSU is that like you have IgE against an autoantibody? So basically you're allergic to yourself. Is that how there's an IgE dependent mechanism? Yeah. So this is actually pretty cool immunology. So you have the high affinity IgE receptor. It binds to the FC portion of the antibody. So you've got the two variable ends picking out. Well, they can cross link each other with an autoantigen. So if you take double-stranded DNA or TPO, for example, it can bind to two variable ends and then cross-link, that activates the mass cell. So that really is equivalent to being allergic to something in allergic to yourself? Yeah. So that's the idea of like checking TPO or double-stranded DNA or some other internal intrinsic antigen. So that mechanism is where directly the IgE antibodies cross-link activate the mass cell. Then you set off the cascade, degranulation, and you've got all those proteins driving disease. So that's type one. Type 2B is going to be like IgG antibodies, which can then bind to those same IgE antibodies and act as the allergen and cross-link it. So now it's not allergic to yourself in terms of TPO or some other antigen. It's an autoantibody binding to those IgE's, activating it, and then setting off the cascade. All right. So those IgG antibodies can bind directly to the high affinity IgE receptor and directly activate mass cells. So this makes sense when you say, well, now you've got this convergent mechanism. It can be activated-- BTK gets activated through both of those. So if you have a patient theoretically who's not responding to anti-IGE with Omalysumab, because they have IgG mediated disease, BTK should still work. So it's kind of that idea is it should broaden the ability to capture patients. So this is why IgE is sort of losing favor, right? Because why do we check it all the time? Because you have a therapy that blocked IgE. But you have all these other non-IGE mechanisms. And that's why Remy Brutonib very fast. So within two weeks about 1/3 of patients had well-controlled disease. So I mean, this is the big differentiator there. But you've got a pill taking twice a day. You've got a kinase, which is going to set off the trauma of all the people afraid of the Jack inhibitors. It's another kinase. And not everybody wants to take a pill twice a day. But the fact is these patients get-- it works in urticaria. It works in patients who also have angiodema. It works for type 1 and type 2B disease. And so I think we do push the limits on skin clearance overall. And you guys talked about the safety. I mean, Patekii, 4%. That should be the least of the worries of the dermatologists who see Patekii all the time. None of these patients have thrombocytopenia or blood abnormalities. So I think what the real selling point of Remy is very fast oral option, don't have to have an injection. Get it on quickly and have the medication shut down disease. Totally different. Yeah, go ahead. Well, it's going to be interesting. I think of Jacks. So first, again, for anybody, BTK, totally different from Jack inhibitors, no cardiothrombomic risk. None of-- doesn't have any of the warnings. None of them are just a present, nothing. But I think of Jacks-- and there's data back this up-- if somebody's itch isn't getting better in the first couple of weeks, the Jack is probably not going to work at that dose. And it'll be interesting to see with Remy, is this going to be a drug where I like, OK, if you're not seeing anything in the first two weeks, this is probably not the drug for you. Let's move on to something else, right? Which I haven't seen any data that tells us that yet. But-- Yeah, well, I think we do see an early signal by two weeks. Like I said, I mentioned that third of patients who kind of have well-controlled disease. But their primary endpoint was 12 weeks. And their patients who do even better beyond 12 weeks. So while you have a fast onset-- and we have those patients with atopic dermatitis, for example, on the Jacks, where they start to see improvement, but they don't really peak out until a little bit later. So I think of this as having really its full benefit by 12 weeks, 8 to 12 weeks is kind of the full benefit. But several patients who have maybe more severe disease may take a little bit longer. So I think the big cell, again, fast onset oral works for hives and angiodema. And probably based on what we see in the early trials, probably no major adverse events and really no infections, which is going to be a big change from the non-selective VTK inhibitors that we saw in the cancer space. And I think that's in contrast to duplium app, right? So it's an ingest. But wait, wait, wait. Before we're going to duppy. So Pat, and you're in the lecture we're given here in a few weeks. You're talking about VTK inhibitors kind of beyond or to carrier. What I haven't really looked into it. What other stuff does Remi work in? I think they're looking at it. I don't know if it works necessarily. I think there's a clinical trial in HS. There's other VTK inhibitors. There was one that didn't look great for Pempagus. I think the company that was studying it decided they're not going to continue that indication. But there was another Japanese study, completely different VTK inhibitor. I hadn't even heard of it before. Some of their data starts to look pretty good. I think you have it for-- there's a VTK study for showgrens. They're really just kind of expanding out. This is a really dumb way to look at it. The Jax, and you think of, look what they've done to T cells. VTK is more like neutrophils, mass cells, the diseases where those cells are predominant. We may see VTK inhibitors really come forward as just like we've seen with the Jax. That's my spiel. So Jason, have you worked with Novartis on the other stuff that you're going with Remi, too? Yeah, we have their H.S. study that's coming. We also have their head-to-head, which is Remi Brutonib versus the DuBillium app for ErdiKaria. We have other ErdiKaria studies. But I think of it as VTK is predominantly expressed in mass cells, B cells, a little bit of Bayes of Hills, and actually some platelets, right? So that might explain part of the T-C. Why the heck does it work in H.S.? Yes, because-- It's interesting because the thought has been-- there's been some immunology showing that there's a B cell signal in H.S. I don't think of H.S. as an auto-anibody-based disease, but there are papers out there publishing B cells may play a role. And so you're seeing some of the by specifics now. I'm talking IL-17 and BATH, which is a B cell activating factor. So I think it's a messier disease, so it may contribute there. But I kind of look at these BTKs being different from the other BTK inhibitors because the way it works, it's nuanced, but it binds to an inactive form of BTK. And that inactive form, the Y551 that sticks out when it binds, it makes it unique. It's a covalent bond. So you're binding to this unique part of BTK. You're not binding to other kinase inhibitors, and it prevents upstream activation of it. So that's what keeps it more selective. So we're seeing totally different profile than the non-selective, non-covalent binding BTK inhibitors. So I think that's where Novartis got this one right. Pat and Ferris and the other Remy comments with their questions, Dr. Hux, before we go on to talk a little bit about Dupy. If you have to, well, talk about Dupy and then I'll ask my question. All right, and Hux, I'm going to give you my, why the hell does, so I believe that Dupy works in CSU because it generally shifts your immune system away from a Type 2 TH2 phenomenon. That's my best guess. But like I've been on ad boards with you where we're like, we don't know why it works. It could be this, there's a lot of reasons it could work. But what do you, what's your guess? Why do you think, if I had to pin you down, of all the different hypothesized ways, what do you think? Yeah, I mean, there's very few drugs where we know exactly why this works. In fact, companies do this all the time. They're like, you know, when it's not clear that this is the exact mechanism by which it gets this disease better. Like we see this all the time and these is generalized, pushler, psoriasis. You know, this exact mechanism may not be known in the way it works. And so I think we have to be careful because we're doing human clinical trials. We're not doing mouth models and in feature studies. But I think we have to look back at that clinical date and we can make some. I can't stop dancing around Hux. What is it? Here's your guess. I think what we're really looking at in Urducaria, we clearly have activation of mast cells. We clearly have a role of auto-anabodies and we have type two cytokines which are elevated in legional and non-legional skin. So when we look at Urducaria, we kind of see those pieces. So when you block IL-4, for example, IL-4 is the main driver of type two differentiation. The mast cell is a type two cell. So by blocking type two, it's the main signal for type two differentiation. In the same way that blocking IL-23 is the main signal for type three inflammation. So we're blocking the production of differentiated type two cells, which includes the mast cell. I think that's number one. Two by blocking IL-4 and 13, we're blocking isotide class switching, which is the production of IgE, which accounts for the type one immunity, as well as other antibody. So if auto-anabodies play a role, you're going to reduce that with dupliumab and that's one of the other mechanisms. Interestingly, mast cells that are activated, once they're activated, they degranulate. Those are the preformed proteins, histamine, tripdase, etc. But then after that, they start to up-regulate production of cytokines, including type two cytokines. So they directly make type two cytokines. And I think the last thing is that all these other cells that come with type two inflammation, we've got baza fills, we've got eocinophils. They can also make some of these other signals, right? They also have BTK signaling. And I think the direct component of these cytokines on itch. I think Prigo nodularis is a good example where it's not just IL-31, IL-4 and 13 can activate the nerves. So we do get some neural sensitization. That makes sense from itch, right? It's not just IL-31. We see itch drop in our atopic dermatitis patients on DuPillium Mab. So I think these are some of those core points that I think you can make sense of why it might work. Again, it's a little more indirect, but our immune system isn't linear. They're always there. It works a lot of different layers. I always say that people you should listen to least are basic scientists. They have no idea what they're talking about. It's not a translational scientist, so I'm not a basic scientist. Exactly. Because the basic scientist just say this cytokine is elevated, so it's in this disease. We don't know if it's, we don't know if anything is an innocent bystander or pathogenic until we have an antibody that blocks it. That's when we find out if it matters or not. Well, what'll be really interesting, I think, to tease this out. When we have other drugs that work by different mechanisms, we start to learn about the other ones, right? The fact in AD where we can block 4 and 13, then you just block 13. Then you just block 4. Well, 4 didn't work in AD. 13 does, but 13 doesn't work in things like food allergies and asthma. We're learning about the role of 4 there. I think in the same way, I think it's unlikely that aisle 13s would work in Urducaria because I think aisle 4 is tied more to that type 2 pathway. That will help us. If you see a drug that works in Urducaria, like DuPilliumab, but not aisle 13 inhibitors, then that helps tease out some of the mechanisms. We can still learn by going backward, but here's the clinical data with Urducaria for DuPilliumab is that they, right, they measured the itch ISS7, was their primary endpoint, different 24 weeks, secondary endpoint UAS7. The UAS7 is still Hives+ itch. The fact is they reduced itch and hives very similarly to some of these other Urducaria mechanisms, right? I think we have, that's a pretty good metric because the HSS7, that's Hives. It's either zero, no Hives. One is less than 20 Hives. Two is 20 to 50 and three is greater than 50. They had a 10 point reduction in that score, which is just the formation of Hives, which is what we're relying on clinically. So that worked. So I think that's the proof in the pudding first. And then we work backwards like, "K, well, now how do we explain this?" But that's how the Translational Sciences work. Let's help patients. Then let's work backwards to try to figure out how it works. I think that's where we're at with DuPill right now. So Ferris, you started that. Go ahead Ferris. So here's my question. All this antibody testing that we're like, "F, it doesn't really matter because it's not going to drive what we do." But now when we're going to have three options, do you think there's going to be some predictive value? The people who have elevated IGE are going to do better on a BTK inhibitor. The people who have IGG driving this are going to do better on DuPill. Do you think that maybe we'll be able to use this to help us pick the right drug for each patient? No. I don't know if you mentioned it before. Good question Ferris. Great question Ferris. That's your mind. Anyway, here's why I'm saying this. Your question is very important because what we don't have in dermatology, even in diseases like serastrate, top of dermatitis, is the ability to predict a patient's response to a therapy? It's still try and fail. It's like a lottery system and so on. We know there's a higher likelihood that you'll respond to some of the newer therapies, for example. But I think we need that biomarker. What's interesting in Nerdicaria, both Novartis and Regeneron Sanifi have data showing that your response is independent to VIGE levels. DuPill is the cutoff of less than 100 and greater than 100. Then Novartis looked at it at lower levels. 40-45 is a little more clinically relevant for IGE levels, but actually internal data within Regeneron Sanifi show that it actually doesn't matter. IGE levels as a biomarker or predicting response to either of those medications were not the case. So I think it's actually challenging this idea of the diagnostic value or predictive value. It might predict response to Omelizumab, but to Matt's point, who cares if Derm is using it? What's the point in checking a lab test? I think there's not good data that elevated IGE predicts response to Omelizumab, but maybe you guys can remind me I haven't looked at those papers in a while. I don't think it does matter. There have been its myths, but there are studies showing that people with low IGE levels don't respond as well to high IGE, which makes sense in terms of mechanism of action. But ironically, there's also patients with really high levels of IGE who also don't respond. So it just shows you there's other immune circuits that can help kind of drive disease. So it's not the end all be all. We need good biomarkers, but I think here we're going to basically be choosing therapies that either one we're comfortable with. It may be comorbidities. So I think on the Dupy side, they take a little longer than Remy. They probably peak out between week 12 and week 24. Week 24, they read out, it takes a little longer for this to kick in. It's a more indirect mechanism. But the safety of this medic. the familiarity and germ. This is already taking off. If you start to look at the data right now for the use of it in Erdicaria, it's actually tracking very close with what we're seeing with what A.D. launch was with DuPamM. So I think the uptake in derm is already really doing well. I think derm just needed to get access to something. And I think these patients that come in with asthma or mild a topic dermatitis or other type 2 comorbidities, which we know can be common. I think this is going to be an option where people already have that success. Your point, Matt, the BTK is new and it's different. That's going to give some people some reservations. We joke about who writes duplicated Matt that's even the people who don't write biologics. Right? So there's a very high comfort level that I think is going to be an off set, maybe their choice for Remi Brutonib. And I think having multiple options is always better for these patients. But I don't think we have good predictors of why should I use this versus this because they both work. They both work pretty well when you give them time to act. All right. Well, Pat and Ferris, unless you guys have anything else you want to ask Dr. Hawks where I think we're ready to kick it over. Dr. Pat and you better have some trivia. Dr. Hawks, I don't think we warned you at the end of every episode we have Dr. Pat and puts together some trivia related to the topic for us. The rule is you got to let them finish the question once he finishes the question. If you got an answer, you just shout it out. All right. Well, the category is hive. So let's go. The musical band, the hives, hails from what European continent? Europe. Europe. I'm going to go with Europe on that one Tim. Next question. Let's narrow it down. Part B. Which country? Switzerland. Belgium. It's Sweden. Ferris, did you know that it was at a guess? We actually brought up the hives before, but they're one of my favorite groups. And if you ever have a chance to go see the hives live, absolutely do it. And we're going to go to the next one. We're going to go to the next one. (upbeat music)