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Hi, everyone. So uh the next speaker I have uh it's my absolute pleasure to re uh to introduce um cause he's from my own institution from Robert Wood Johnson Medical School doctor. Um He is really a giant in the field of pulmonary medicine, specifically in asthma, um asthma translational research specifically and to give you an idea of how much uh of the type of impact that he's had um on our field. Uh My CB is probably like six or seven pages in total. Um His original publications alone were 25 pages like 25. II counted it out like multiple times because I was like, I don't know if I'll ever get there. But anyway, um he's served additionally on uh numerous national grant review panels, major committees as an editor on a number of journals, including the co editor in chief of the journal Respiratory Research. He's mentored and advised well, over, over 100 trainees, I saw the list of names. Unbelievable. Um And at our institution, Robert Wood, he's the Vice Chancellor for Translational Medicine and Science and the director of the Rutgers Institute for Translational Medicine and Science. And I really could go on and on and I really thought this is gonna be simple, but it, it wasn't um because it was just so much on there. Uh But to get to the point, he's really offered uh generously offered his time to discuss how monoclonal antibodies uh improve the management of patients with severe asthma. So please welcome me in. Welcome, Doctor Terry. Thank you so much for being with us. Thank you so much. Well, it's a real pleasure to be here and very exciting. Um So I also stand between you and lunch, which is really a formidable challenge. So I'm gonna cut short. There's two things I want you to remember. Only two things. I've got 40 slides, but two things. One, pharmacodynamic biomarkers predict therapeutic response with biologics, pharmacodynamic biomarkers predict the therapeutic response to, to uh to biologics. And number two, the real world data, real world data in biologics absolutely mirrors randomized controlled trials. That's a shocker because we all take care of patients with all the comorbidities that are excluded from every randomized controlled trial. But the fact that RCT S could be validated with E hr is really important. These are my disclosures. None of these uh will impact on my talk. However, if anybody else wants to work with me, please reach out uh one other thing I wanna stop here and recognize the sponsors because whether you're at ATS whether you're at chest, whether you're at any meeting, these meetings wouldn't happen without the generous sponsorship that is given by industry. So let's take a minute and clap. Thank you. Ok. So what are we gonna talk about? We're gonna talk about severe asthma, what it is? We're gonna appreciate the burden. We're gonna talk about key pathways that regulate airway inflammation and characterize monoclonals as we know. And there are six holy cow. That's a lot, but we're gonna lump it all together. So, what severe asthma? You all know it, you talk to these patients day in and day out, usually over the age of six on high dose I CS. And despite that, still have symptoms, er, visits and hospitalizations, cocktail party conversation, how much have we impacted on er, visits and hospitalizations from 1970 to current? Now, think about that 1970 I mean, some in this room weren't born. But let me tell you that I CS lava came on board then, wow. And then biologics, one after the other, the first one was on Melizame 22 years ago, 22 years ago. So I don't believe that. Right. But the important point and since 1970 we have had zero impact on er, visits and hospitalizations. So we're doing great in asthma, right? Asthma is uncontrolled despite our therapies and we need to understand why. So the chronicle study, this is uh one that I've been involved in, has shown that physicians believe 60% of our patients are well controlled but if you use the asthma control test as a metric of success, 53% of our patients are not well controlled. So there's a disconnect. So when you ask the patient, how are you doing? And they say fine, they're not fine. You need to get more granular with regard to how they're doing. So, the asthma control test is very helpful for that. Now, it doesn't, can check, it doesn't capture the er visits and hospitalization. So you have to ask another two questions over the five questions. Less than 19, you're uncontrolled, greater than 19, you're controlled. Now, one of our challenges is this slide, the heterogeneity of disease, the heterogeneity of disease is not just manifested here, but our sleep expert highlights the heterogeneity of sleep. We use one word asthma, sleep disorder, diabetes. That's not one disease. That is multiple diseases which we use as a shortcut. Matter of fact, if you're on cardiology rounds and you say the patient has congestive heart failure, what would the cardiologist do? Well, what about the other four adjectives that go with congestive heart failure, valvular disease, uh hypertrophic uh cardiomyopathy. So the point is we as pulmonologists have to use adjectives when you talk about asthma. What is asthma? Asthma is a topic? It's a, it's a, a atopic allergic or eosinophilic or paucigranula. So, on rounds fellows, when you say it's asthma, tell the attending, it's atopic eosinophilic asthma and you're gonna have much more granularity in the disease process. Now, what causes asthma and severe asthma? Well, this is just one iteration. The environment and gene interactions induces asthma. But every asthmatic also is exposed to injury and we posit that the abnormal injury repair response which is genetically determined can spin people off into irreversible airflow obstruction. Now, maybe some of that has to do with remodeling. I don't think so, but it does suggest that recurrent injury repair responses whose function is this is, is not correct will lead to potentially irreversible airflow obstruction. I wish it was that easy. It's not just genetic, it is also epigenetic. What's that mean? That means the environment can fundamentally change your genetic code, that's inheritable to your progeny. That's shocking. So what's the perfect example of that? The mother who smokes the mother who smokes can epigenetically pass that injury on to her Children that then propagate an asthma gene. So it's not just genetics, it's environment also. Now we all as pulmonologists are faced with this. What is this? This is irreversible airflow obstruction in asthma. I'm gonna tell you the tale of three stories. C is a patient who developed asthma under the age of two, had a profound injury, but then repaired and felt better. Now, the progression of that patient's airway function was attenuated. They never reached a which was the normal development in their lungs. So they kept going their merry way, they felt fine, but they crossed the line of disability at about 50 they come to your office saying I had a viral infection and now I can't breathe. I'm short of breath and everything I've done doesn't work. And I'm on steroids all the time. You go, oh my gosh, whatever that was injured, you that made it irreparable. Well, truthfully they were already on this curve never reached the maximum function. And because of the inexorable loss of lung function over time crossed into disability. So what they lost, they lost early in life. Ain't gonna get that back. What can you do? Well, you can prevent exacerbations of asthma which could hasten the decline. B is an intermediate phenotype, took a hit early on, never reached the maximum and then started to decline. So the important point is when you see the patient with irreversible airflow obstruction that may have occurred early in life, only realized later. So heterogenetic disease manifestations and severity, but there's also heterogeneity response to therapy. So if I give this half of the room 20 of predniSONE, some of you will develop cushingoid symptoms and others won't. That is genetically determined by your response to therapy. So there's heterogenetic response to therapy, heterogenetic disease. It's amazing we have drugs that work frankly. Well, this is humbling because this was a study done by and colleagues and what they did is they compared me to Singulair and this is common in every drug you use. There is a Gaussian distribution for response. Some people have remarkable responses and the white here is actually be meth. The patch mark is Singulair in the use for mild asthma. What was recognized is 55% of patients don't respond to an inhaled corticosteroid. 55% don't respond. Yeah, inhaled corticosteroids. This is the cornerstone in the management of asthma. And I'm telling you the majority of patients don't respond if you use the one that is a Gaussian distribution of therapeutic response to any drug we use. So there's lots of shortcomings in the treatment of moderate to severe asthma, incomplete control of symptoms and inconsistency of efficacy becomes problematic. Matter of fact, biologics which we feel work tremendously well in severe asthma, they only decrease exacerbations by 50%. So take the other side of the coin, 50% of patients are not gonna get an improvement in exacerbation to a biologic. And that we consider a great success. When it's a coin toss and improvement O CS therapy, we use a tremendous amount of oral corticosteroids way too much and that impacts on quality of life and functional status of all of our patients. So keep that in mind the critical question, despite improved understanding of asthma treatment and targets, the availability of several biologics still is not where we want a matter of fact, less than 10% of all severe asthmatics are on a biological, less than 10% you could say if we take T two high severe uncontrolled asthma, maybe 70% of those patients should be on biologics. So we need precision therapy. What is precision therapy? Right? Diagnosis, right. Patient, right. Therapy at the right time. And this is sort of my confusing gram. I'm using Mike Wexler's term uh from National Jewish. Uh So what you do is you take every set of kind, you know, you put it on a board and then you put a lot of cells and say that this is the critical one. But it does give us a comprehensive glimpse into the complexity of airway inflammation. We're gonna take some of these and group them. Now, biologics are underused in patients with severe asthma, mostly because of the low T two in the audience with all your pulmonologist me included, we see a whole lot more low T two patients that is patients that don't have IO 13 IO five and IO four consequences or Eoin why? Because all our allergies colleagues for them to us and call it CO PD. I can tell my allergy colleagues, the patient never smoked. The only way you get CO PD in the US is if you smoke, so they don't have CO PD, they have uncontrolled asthma that again could occur early in life. But the important point here is only 23%. These are CSU S remains high as we go through looking at the group of patients. Now, we did a study at, at Robert Wood Johnson. This is actually a medical student helped me. And we asked a very fundamental question. How many times are biomarkers used in the management of severe asthma? We uh we uh sampled our E hr Epic. And what was fascinating is I GE was measured in severe asthma. 10% of the time rash, skin test, no test, 38% more than one test. 10%. 10%. What are the three tests you should do in patients who have severe asthma, at least the diagnosis and follow up what's gonna be feno it's gonna be blood eosinophil count and I GE and R those are the three biomarkers that should be used. Now look at this eos were done 62% of the time. So you can say, oh Thanet, we're on on target, we're measuring it a wrong. This was primary care doing CBC simply for health maintenance. The data was in the chart but nobody looked to see if the patient had eosinophilic asthma. So important point is you often have the data right in the chart. If you look at it for blood eosinophil counts as a biomarker that could be pharmacodynamic biomarkers. So what are the biomarkers we use? What are the key and relevant updates in G A&E N EP guidelines? We're gonna cover those. Now, the guidelines recommend blood eosinophils. If you're greater than 150 qualifies as eosinophilic asthma, pheno greater than 20 is uncontrolled airway inflammation, sputum eosinophils, none of us really measure it. And then I would do a rash test, rash test and specific IgE tells you if you atopic, not your total I ge total IgE just was a marker for the use of a melizam. It doesn't tell you for atopic. Many of you of you have done an IgE and it comes back 500 you say, wow, patients allergic, you didn't do specific rash, specific IgE and they're negative to everything that patients not atopic. Keep that in mind, atopic is specific IgE. Choosing a biomarker by uh choosing a biologic by biomarker is critically important. You have to do the test and then think of comorbidities and the comorbidities are listed here, won't have time to go through all of them. But the ones that you need to know about is nasal polyps, chronic rhin sinusitis with or without nasal polyps. If your EOC count is 150 have any of these comorbidities, then that would put you in the T two inflammatory group and therefore you should think of therapeutic management. So I wish the gene and guidelines got simpler, but it didn't. So there's a couple of categories here. The anti I GE we've had that for 22 years. We're all familiar with Melizam. It works in some what it doesn't do though is move the FE B1, the anti I five Mepolizumab, reslizumab and be Melizam. These are very effective. These are anti eosinophil drugs like greater than 150 and, or chronic sinusitis and polyps. That's a great drug anti il five receptor antagonist that targets the alpha receptor of IL four. It's a receptor antagonist and this is gonna be Dalima very effective in comorbidities. Uh And then the most recent is anti TSLP. You don't have to have a biomarker to start uh TSL P but biomarkers are very effective in showing therapeutic response. These biologics all listed here also are effective and approved for a variety for a variety of comorbidities as demonstrated here. So let's talk about anti five me re and Benralizumab. This is not in order of efficacy but in order of temporal approval by the FDA. So eosinophilic asthma, most patients about 70% will have EOC counts greater than 150. So they could be a candidate for this therapy. The worse eosinophil more eosinophils is associated with greater exacerbations. These are the way the drugs work. Mepolizumab and reslizumab bind the ligand. Take the ligand out of circulation doesn't allow it to bind to the receptor. And therefore, because eosinophils need L5 to live and to migrate, they don't live and they don't migrate. The other drug which has a unique mechanism of action is Benralizumab that binds to the receptor on the eosinophil. Now, why is this cool? This is very cool because at the end of that molecule, there's a beacon like a lighthouse that signals the natural killer cells in the body to bring the natural killer cell in and implode the and it's so effective, it wipes out all eos wipes out all eosinophils in the body. And that happens after one dose. It's a very effective novel mechanism of action. These are the anti fives in the early days, first studies. You know, when G SK uh uh was bringing this into development, they did this study, this was a lucky study. They gave an anti five and my and uh uh they gave melizame to mild asthmatics and lo and behold, what they showed is that you could block eosinophils effectively, but you had no effect on airway inflammation and didn't have an effect on exacerbations. This would have killed the drug, right? No, what they saw is that they went after mild asthma instead of severe asthma. When they pivoted towards severe asthma, they were able to not only demonstrate a profound effect on exacerbations, but also could spare patients, could spare patients, oral corticosteroid birth that's shown here is placebo looking at patients without an exacerbation. So higher is better. This is baseball, football, not golf. Uh And Mepolizumab really was quite remarkably different in placebo. What did this teach us? This taught us when you find the right drug for the right patient at the right time. It works when you try to use it across all cases, it fails. So this was a great lesson in precision medicine. Mepolizumab had a profound effect on exacerbations specifically. And those patients with high eosinophils, you can see placebo here. Now, lower is better. So this is truly golf and you can see mepolizumab decreased exacerbations. It also improved AQLQ. Uh So bottom line, this became very effective. Reslizumab then came out, this was an IV formulation based on BMI. They looked at a 52 exa 52 week exacerbation study and you can see higher is better here, probability of not having a uh an acute exacerbation. So higher is better versus placebo and reslizumab work. Now, this is IV and it's BM I determined. Now there has been very few head to head comparisons. This was one done by uh in Hamilton uh where uh par had looked at me o people on me uh for uh 12 months and then was crossed over the Reslizumab. And they looked at the benefits of this. It was very interesting study. What they could show is sputum ils in the presence in the presence of Mepolizumab uh didn't really go down significantly. But those patients that in the subsequent time got reslizumab. Remember this is IV, actually profoundly dropped the number of eosinophils in the sputum and the blood eosinophils. Now, blood eosinophils, the me went down. Also what they then could show is if they looked at activation markers of the eosinophil is that the reslizumab was a bit more effective. Whoops, then mepolizumab, which was interesting because again, the bioavailability of wiping out the eosinophils in the presence of re seemed to be better, seem to be better than Meli. But what the investigators didn't show is an improvement in the exacerbation rates. So the eosinophil is important uh and eliminating it is helpful. Now, I talked about a pharmacodynamic biomarker. What does that mean? That means you engage the target and you have a consequence. So if I have an anti il five drug, I give it to a patient and I measure the blood eosinophil count and it's zero or goes down remarkably. That means the targets engaged. It doesn't mean that the patient got better. But what drug do you use now where, you know the target's been engaged as a pulmonologist, we have very few therapies. What we look for is an improvement in outcome. But I would say the negative experiment is just as important because if I eliminate the E OS and the patient is not better, what did that tell me? Eosinophil has nothing to do with asthma, I kill the drug and I move on to the next one. Think of where you do that now where you know, you've engaged to target and can kill a drug and move on. That's called precision medicine. So I'm thrilled when I know the eo has nothing to do with asthma. And I tell the patient, hey, I got great news. The eosinophil has nothing to do with your asthma. And they said, well pan, I'm still sick. So it would come to that. But the point is with confidence I can move on to the next drug. Now, Benralizumab I mentioned is unique because it binds to the receptor to which IO five binds. And then the tail of that signals natural killer cells to kill, to kill the eosinophil. And you can see it profoundly worked in their uh registration studies with a, a drop of about 50% uh in exacerbations. And even those under 30 under 50% had an outcome. What it also showed is the median change here in oral corticosteroid dose. So when you are on Benralizumab and me O has shown very comparable data that there is steroid sparing that you could decrease or corticosteroids. You can also look at time of first exacerbation. In this case, you see you have it by 50% very similar data across the board. For all biologics, you give a biologic and you can decrease the exacerbation rate by 50%. It doesn't mean it, it doesn't matter if it's Mepolizumab or Benralizumab. So the spectrum of biologics are shown here, omalizumab balance IG it doesn't typically improve the F EV one but predictors of response are shown here. And you can see with L5, it's really the eosinophil count that drives it. In the case of the pab targeting L4, it's feno and blood, the eosinophil count and he doesn't need biomarkers. But I'm gonna show you engagement actually decreases the biomarkers. What is the benefit of all these drugs while it all decreases exacerbations, all improve patient reported outcomes. Quality of life. Most improve F B1 except for on melizam does not profoundly improve the FFB. One quality of life goes up and most have improved O CS. Although with reslizumab, that study was never done. So we have alternatives. Now. What about way upstream? The alarms, TSL P 33 and IL 25 are secreted by epithelium that then drives the downstream signaling. Teab. You don't need biomarkers, but I highly recommend you checking biomarkers afterwards because after one dose of teab, which targets anti I which is a anti TSLP drug, eosinophils drop and actually pheos drop. And what's quite remarkable with Tez Ailim, although the time course is delayed by three months, it decreases total IgE levels. This is the first time that a drug can actually profoundly decrease, decrease that outcome. Now, teab also has the ability to decrease the eosinophils in the submucosa in a biopsy study and, and decrease airway hyperresponsiveness to Mannitol. Whereas the data for anti I five haven't changed. A hr has Ailim. Uh pivotal trial is not gonna go over all these but not uh pathway and navigator were there. And you can see these are patients who are pretty profoundly affected by their um by their fev one at 60 63%. S sorry. There we go. And if one looks at biomarkers again, whether you're greater than three, greater than 300 less than 300 or less than 150 asthma exacerbations teil went down remarkably. Now, it did work better when you had the more yields. So a high T two actually predicted better therapeutic response to teab, but it also had nearly 50% drop in what we would call low T two. And that would be with low feno or even with allergy. So, Teab also has the ability after the first dose to improve the F EV one, which is quite remarkable and patient reported outcomes also improved. This is standard of care to teil and the A CQ six lower is better and you can see it improves the quality of life by AQ LQ goes up. So exciting time, let's talk about now the recommendations. So g as well as the guidelines says, OK, if you got severe asthma, pick a biologic, do it precisely driven by biomarkers. If you start it for the most part, they recommend four months, I'm gonna refine that and show that you can actually get an answer quicker than four months. If it's a clear response, then you're gonna consider continuing, if unclear, then you would consider changing. Is there more specific guidelines on time? Course? Here you go. IO five drugs work quickly. It doesn't matter if it's Mepolizumab doesn't matter if it's reslizumab or Benralizumab. Matter of fact, in four weeks, how many doses is that one, you could determine an improvement. The F EV one, the ability to improve patient reported outcomes in the act test. Now, the anti il four receptors that takes about 12 weeks, as does the anti TSLP, both of those can affect the IgE that takes longer if you have the allergic asthmatic. So if I started that drug or I've switched that drug, you may wanna consider that the anti IgE E is at least four months or greater before you can determine outcomes. So, can we use particular tests? I use the asthma control test all the time. I use PF TSI measure feno at every visit in our outpatient practice, blood eosinophil counts. I only do once uh to determine they have eosinophilic asthma. And then after I've started the anti five or T uh or an anti TSLP, I check again blood eosinophil counts to see if they've gone down. That's pharmacodynamic biomarker. And that guides my approach. What should you ask your patients? And really one of the most important questions is to do shared decision making. It's amazing when you talk to a patient, what they value many times they value just an improvement in their quality of life to be able to play with their grandkids. They don't care about their improvement in the FE B1. They want to do normal things. Maybe another patient might not care about any of that, but get off oral steroids, asking the patient what they would view as success is incredibly important because the shared decision making, engaging the patient allows you to tailor in a precise way to therapy that they'll value if they value the therapy, guess what their adherence improves. So we wanna reduce O CS, we want to improve activities of daily living. We as pulmonologist always consider improving the fu one but we wanna decrease exacerbations. Remember what I said? Every time you get a exacerbation, if you have susceptible aberrant injury, repair response, you lose a little bit of lung function. So when do we switch, when do we switch? Well, these data were done by Menzies's gout and they showed that 79% of patients are continued on their first biologic, whether it works or not. The reason is because we have a heavy lift to get preauthorization and we have an inertia in getting rid of that drug. They about only 10% ever stopped completely switch biologics about 10%. And the switching here doesn't really have importance because it depends on what new drug has come out considerations for long term care. Well, as I mentioned, 22 years of Omalizumab, we've had eight years of Mepolizumab, about five years of Benralizumab and about two years of Tezepelumab to pili in between every one of the companies have had continuation safety studies. Actually, Ben Melizide has data. Now in the study for five years showing absolute safety, these drugs are incredibly safe. I really have not had complications from these medications and the data is really supporting it. Now, what about Real world data? Each and every company has now searched the E hr and done the following study. The index time is the start of the biologic. Well, 12 months before 12 months after and what each and every company has shown with each biologic is that they are randomized controlled trials were echoed in real world data that leads itself to real world evidence. It's exciting. So what can you predict when you get the right biologic for the right patient? 50% decrease in exacerbations, not 100% but 50%. That's group mean data. I know you're gonna put your hand up and I've had some people that's never had an exacerbation again and they throw their inhalers away. Uh Yeah, that's miraculous. But that's when you look at the aggregate data, you can predict a 50% decline. So good control versus achieving remission. What is asthma remission? Asthma remission is completely asymptomatic, no exacerbations, no oral corticosteroid therapy on current therapy. And you could be very poorly controlled, moderately controlled or well controlled, complete remission is what we strive for. This isn't lung cancer, right? So the concept of complete remission is a little foreign for us but is remission possible. The answer is it is, does pa a patient meet all the following criteria as we would call them an Uber responsive patient? Right? Not a Lyft response, but Uber response and what we can see here is no regular CS, no exacerbations, normalized lung function, feno low and control of comorbidities. Now, many of our patients don't fit into this category. And if they're nonresponders, you're gonna kill the drug, you're gonna kill the drug. I'm measuring the pharmacodynamic biomarkers to no engagement if engaged and it didn't work, then that particular biomarker is not predictive. So that's very important. So what I would say is that asthma is a spectrum of diseases, heterogeneity, not only in response but in therapeutic approach, increased understanding of our immunology has been great and it works to decrease 50% of exacerbations in patients with biologics. Far too few patients with severe asthma are on biologics, defining the endo type is a young field but making progress and tailoring the patient's phenotypes to their goals are important. I wanna thank you all and not too far off lunch. So great to be here again. Thanks as sponsors. Yes, a piece of candy. Do you see in the also there? Um OK. So multiple questions there. Yes, I measure phenol every time because I have the availability of doing it. And I find it fascinating um if patients are taking their I CS, no biologic right now, the feno should be low. If the feno is not low. Uh And you know, they're on a high on a, on a ICS lava. Then the questions are they adherent or are they steroid insensitive? Remember the slide, I showed you 55% of patients don't improve on an inhaled corticosteroid. So if they're uncontrolled and they're high feno, then I think of ale 13 and A L4 driving that that case. Also, the eosinophil count is helpful. So, eosinophil count of 50 while patients on 10 of predniSONE, is that abnormal fellows? You bet you right. That's abnormal because if you took the steroid away, it could be 300. So very important that if a patient's eosinophil count is high while on oral steroids or present, either they're not taking their drug or they're steroid insensitive. In that case, the perfect drug would be an anti five, right? Because take out the eo and all the studies have shown except for the reslizumab oral corticosteroid sparing. So there's a, a way that I would use it. Now, there's instances where I've had patients who have high pheos despite oral corticosteroids, which is here. I don't understand that either. They're not taking their drug and sometimes they're not cushingnoid either. So I don't know if they are poor acetylator of predniSONE or maybe Medrol would be better. But, but you know, the feno does inform me and I like using it because it gives me an idea of adherence and it allows me to figure out what's the next step. So I use it. Yes. Uh I OK. That is so. No, no, I didn't mention it some people would consider it. I never take it. II look, when I, when, when I start a biologic, I tell them we have no idea about the end game. There's no data to support that you stop this or expand the times timelines or any, there's zero data. So II like I like to not overpromise and under deliver. So if I start this and it works, I'm probably gonna continue this as long as I'm with you now, patients will opt to poor stop their adherence. Um And that tells me volumes. It's not that the patients poorly adherent. It's that the drug ain't working because a patient who really, really benefits from a biologic will never stop their biologic. If they are willing to stop their biologic, you got the wrong drug. So pick a pick another drug. It's telling you value so poor adherence is often poor provider choice, not poor adherence. So keep that in mind. So I don't know if remission is really a reality. Every study that has been done where they've stopped the biologic, the disease has come back. No study has shown a moderation or, or, or an effective change in the course of asthma to date maybe with drugs like tzomet uh in with longstanding 5, 10 years or complete deletion of the eosinophil for 10 years. Could that be curative? Uh don't know uh in the back and you had your, you start the biologic and they love it and now they can do anything but they don't wanna take them. Yeah. Yeah, that, that's not what I tell them. I said you're gonna stay on your ics lava. Uh, I may decrease it to a minimal dose but I haven't recommended stopping standard of care on top of it. But, you know, patients are adults sometimes and they do what they wanna do anyway. Uh, including my brother. I started him on, on an Ati Il five. He had terrible asthma. And then, you know, he's recalcitrant, doesn't wanna see me on a regular basis. So every year he calls me and I said, well, I need to, you know, also renew your I CS lobby. So I stopped that two years ago. Uh, do you care to call me? Let me know. I mean, I see a family functions. He says I don't need it. So the point is, is when you get it right. You know, some of these other therapies could be moved to P RN sort of smart therapy, which, you know, patients are doing that anyway. Uh, we're naive to believe they're not doing smart therapy and we have new choices in drugs, right? The newest drug is Budesonide and Albuterol out there that could be used. That's P RN, uh, here and then in the back then, yes, the work higher up and it's, he doesn't need any exercise. Yeah. Yeah. Uh, it's a great point. It's a great point and I wish life was so simple and their data is gorgeous. But in the real world, what I've seen is less than optimal decrease in eosinophils. If you looked at their Y axis, it was about a 50% decrease in the eosinophil count. So they didn't wipe it out and it hasn't been uniformly 100% responsive in, in patients that I've started as a pill. Now, when did we all started? We started it in low T two patients which are incredibly difficult to treat because low T two means no T two biomarker. What a horrible case definition. The lack of a biomarker is the definition of the disease. I, you know, the epidemiologists are rolling in the graves over that case definition. So uh it, I wish it worked in everyone. It doesn't work in everyone. So if I've got a really eosinophil patient, I'm gonna use the anti five first cause I wanna get a yes, no answer. And then I always have Teab as, as the backup cause I'm always looking for the next choice. Also, it's not simple. I've had a lot of people on Omalizumab. It was the best, best thing that to sliced bread. And then sure enough, 10 years later, it's no longer working and they, their immunology has morphed from a eosinophilic or an allergic allergic immunology to an eosinophilic immunology and the omalizumab doesn't work there. II, I've been around long enough to watch natural history. Unfortunately, of these patients and their immunology changes and then I changed the biologic. It was thunder. Yeah. And what's the experience with it in terms of those are the most? Yeah. Yeah. So your Yeah, these are the, these are real challenges. So this one that is the anti TSLP is the first one to show the efficacy in the low T two. But again, only about 50% of those patients respond. I can tell you where it doesn't work. And we share these patients obesity, you know, that's the perfect low T two anti-inflammatory patient. And I've not had very uniform response to the test. So, so I wish it did but it didn't. Um I always look for comorbidity. So in the low T two, be sure that the patient really has asthma, make sure that they don't have other comorbidities that are complicated. There was a question in the back and the last one here, one more question. Yes. Sure. All the way in the back. Yeah. Mhm. And it's hard. Not too bad for me. I um yeah. Could you repeat that? I had a hard time a little better yet. Yeah. So yeah, that. Ok. Yeah. Yeah. Yeah, it's a great question. So let's talk about special, let's talk about special populations, Children, some of these drugs are approved in Children now actually just got their 66 month uh uh down to six years approval. So for pediatrics, there are specific drugs that are approved what about pregnancy? There is no drug that's been approved for uh biologic and asthma in pregnancy. What do I do? I continue to treat right through pregnancy with it. Each and every company has registration, uh a registry and you could always tap your medical liaison from the sponsor and ask about data. We've not seen consequences in treating patients with biologics who in in women who are pregnant. So, you know, I think of fetal wastage as being poorly controlled asthma is a greater complication. Think about an asthmatic uh uh pregnant women who have an asthma exacerbation. We use high dose steroids which is known to cause thinning of the placenta. I am more conscious of controlling their asthma in pregnancy then not. So I would continue to treat through it. Right. Yeah. Yeah. I, what I would tell the patient is that there's no data of safety in this uh using biologics. But I know that prior to using the biologic, you were miserable and I know that predniSONE is not good for your baby so we could take you off this. But then I'm gonna have to treat you with predniSONE, which could cause more complications than the biologic. But I'm honest, II, tell them there's no studies that have been done on the safety, but there are thousands of pregnant women who've gotten biologics and asthma not seen a big signal other than I otherwise they would have had to report that. All right.