Good morning, everybody. Thank you for waking up early. It's very hard on Tuesday. I thought that Monday was the hardest, but Tuesday is even harder. So our first speaker is Dr. Khurana from University of Rochester. She's going to be giving an update on the management of type 2 asthma. Thank you. Thank you so much, Dr. Adrish, for this invitation. And thank you all for being here. And when I first got this topic, I was like, this is great. There's so much good stuff. There's so much cool stuff to talk about type 2 asthma. But then I realized I had 15 minutes to cover it all. So we're going to go really fast through this. These are my disclosures, no industry relationship. So let's just start with, what is type 2 inflammation and asthma? What is type 2 asthma? And Gina gives us this guidance on how to recognize type 2 inflammation in our patients with asthma. So blood eosinophil count, that's greater than 150 cells per microliter. Pheno, greater than 20 parts per billion. Sputum eosinophils, which I think none of us are really doing outside of research setting, greater than 2%. And then if you have evidence of elevated IgE with allergen sensitization and asthma itself is clinically allergen driven. But they also provide some additional guidance. The first is that these type 2 biomarkers are really very variable, at least for pheno. And blood eosinophil count, it's recommended that we repeat measures at least three times if the first measurement is low. And keep in mind the effects of anti-inflammatory therapies, particularly high dose inhaled steroids and oral corticosteroids. And in patients who may just be coming off of oral corticosteroids because of an exacerbation, wait a couple of weeks before checking another biomarker level. If blood eosinophil count is 300 or greater, consider checking for strontuloides. It's a blood work for antibody titers. I'll tell you, I check it more frequently than I've found it positive. But I did find one patient who was immunocompromised and had eosinophilia that was driving her poor asthma control. And treating her with two courses of ivermectin resulted in excellent control. And we didn't have to go into any additional advanced therapies. Also, blood eosinophil count is greater than 1,500 cells per microliter. We want to check ANCA, look for vasculitis. And then just keep in mind that all these biomarkers substantially overlap. And about 60%, based on the International Severe Asthma Registry data, patients, 60% of patients with severe asthma would have two or three of these biomarkers that are elevated. And immunopathology of type 2 asthma, although I think we understand it quite well, is complex. And I just want to, I think you know this, most of you know this quite well, but just keep in mind that there is, we now call this type 2 inflammation and not Th2 inflammation because of participation from or contribution from the innate lymphoid cell 2. So the Th2 arm is now the adaptive arm. And then the innate ILC2s discovered within the last 15 years make up the adaptive arm. So the Th2 pathway is the allergic eosinophilic pathway. Tends to be childhood onset, early onset with allergic triggers. And Th2 mediated with secretion of cytokines IL4, 13, and IL5. And IL4 drives that B cell class switching and IgE mediated allergic inflammation. So in these patients, blood eosinophils are elevated. That can be driven by all three of these cytokines. Pheno, which is an IL13 biomarker, is elevated. And then, of course, you have evidence of allergen sensitization. While the non-allergic eosinophilic arm is driven by the innate lymphoid cell 2 mediated inflammation, primarily secreting IL13, IL5. So we see more of blood eosinophil elevation and not so much the pheno and allergies. So two sort of potential mechanisms for this. And then there's also, of course, the epithelium. Who all have heard a lot about epithelium and asthma? This meeting is becoming increasingly recognized. We've always known that the epithelial barrier, there is a dysfunction in asthma. But now we also understand that epithelium is actually actively participating in inflammation in both type 2 and non-type 2 asthma. And in type 2 inflammation, it's the most upstream. And these are the alarmants, TSLP, IL33, and IL25. And then we also understand that the mucus in asthma is dysfunctional. So the mucus dysfunction is becoming, again, increasingly recognized. There is excess MUC5AC production, and there's abnormal tethering to the cell surface. So here in the next three slides, I'm just going to walk you quickly about what we all know is already understood, known about these available type 2 biologics. There are six in this space. So very fortunate to have these options for our patients with severe type 2 asthma. These are the targets that, you know, all of us know this quite well. IgE is targeted by omelizumab 3 for anti-interleukin 5 space, dopilumab, which is the interleukin 413 pathway, and then tezepilumab or TSLP, which is the only anti-alarmant. All of these are administered subcutaneously except for reslizumab, which is IV weight-based. And then when you look at the exacerbation reduction, which is really the primary outcome when we use biologics in our patients with asthma, it's about a 50% reduction in exacerbations across the space. And then there's some improvement in lung function as well. And then also increasing FDA indications for other type 2 comorbidities for nasal polyps, omelizumab, dopilumab, and mepolizumab are all indicated. Mepolizumab also for EGPA and hyposynophilic syndrome, and then dopilumab for eosinophilic esophagitis and atopic dermatitis. And what are the factors that predict response to asthma? So this is, again, from the GINA guidance. And as you can see, that it's really, again, there's not great discriminating factors. So it just makes our job of selecting the right biologic for our patients exceedingly difficult. So all of these biologics, the blood eosinophils predict response, phenol predicts response, and all except the L5 pathway monoclonal antibodies. There is, you know, for patients who have early onset or allergen-driven symptoms, anti-IgE therapy is considered a predictor of response, and then for anti-L5 late onset and presence of nasal polyps. Now, since omelizumab was approved in 2003 and since then, since 2015, every year we've had introduction of one new biologic. We've also learned a lot about durability of response. So Nick Nania, who's in the audience, published this long-term follow-up review of 45 studies in children and adults of omelizumab. And as you can see, these are the different exacerbation, sustained decrease in exacerbation. And these were studies that were nine years or greater in duration, and there is a sustained durability of response in these patients. There was this very similar-looking graph for asthma control as well. Similarly, for omelizumab, there's been extension studies that have shown that patients who were in the initial studies dream and similar results for mensa. Up to three years, there's been sustained response. Very similar graphs. I'm going to just show these rapid fire. Basically, this was the Meltemi study for benrolizumab. Again, excellent sustained response up to four years. Dupilumab, a traverse study, again, sustained response. And then more recently, tezepilumab out up to two years. So what we know now is that, yes, we have a ton of biologics. A lot of them are in the type two space. They're effective, and they have durability of response. And there's increasingly now, we're looking at what else can these biologics do. And within the last year, there have been three publications looking at mucus scores and if some of these biologics can impact ventilation and mucus scores and lung function. And this was a single center study from Perm Nias group looking at xenon MRI ventilation in patients who were on benrolizumab out at 28 days, one year, and two and a half years. And as you can see here, these are just two representative patients. There's poorer ventilation in certain areas. And over time, there was improvement and how well it projects. You can see the mucus plugged airway that improves as well. So I think there's going to be more to come on that. Similarly, dupilumab, same center with improvement in the CT evidence of mucus score wall area, and then also xenon MRI ventilation. And then, again, another representative CT from a patient showing improvement in MRI ventilation and also this mucus plug. And then the cascade study in tezapilumab, which was an exploratory double-blind placebo control trial of 82 patients at 28 weeks showed significant improvement in mucus score as well. So now, you know, I think there's really exciting data. I think there's going to be more to come on that mucus and, you know, mucus ventilation piece. And we're really now looking towards looking at remission in asthma. A lot of the remission concept has really been borrowed from our colleagues in oncology and in rheumatology, where when we have somebody who's been on a biologic and has pretty much no symptoms, no exacerbations, could we consider that this is remission on treatment? So this has been a hot topic debated amongst experts. And, you know, recently, this is actually right hot off the press, a consensus statement. This was a three society consensus statement for definition of asthma. What criteria does a patient with asthma need to meet on biologic to consider remission? And these are the criteria that were put forth. So no exacerbations over a year, no missed school or work, less than once a month reliever therapy use, asthma control that is sustained, improved using one of these measures, at least measured twice over a one year period, stable and optimized lung function also at least measured twice over this period. And then their background therapy has to be low intensity, so low to medium ICS with a controller. And then Dr. Lugogo published this with her colleagues in CHEST looking at what percentage of patients on biologic achieve this remission. And these are all the studies. These are the biologics up here. And what you can see here is that about 30 percent of these patients, the prevalence of clinical remission in these patients was about 30 percent. So I think this is really great progress in the space of severe asthma. Those of you in the audience who practiced taking care of these patients before 2015, you know, we really didn't have much beyond Omelizumab to offer. So I think that it's really, things are looking great. But there's still some needs that need to be met, and I've listed them here. We certainly need more biomarkers that can provide more mechanistic insight and help us with endotyping, guidance on switching. And I know Dr. Adrish is going to tackle that in his talk. Efficacy based on comorbidities, so further personalized medicine based on comorbidities, and then impact on airway remodeling and disease modification. And there are some exciting potential future therapies and targets that we may see some of these come to fruition. Depamilkemab is a long-acting anti-interleukin 5 antibody given every six months instead of currently it's being given every four weeks or eight weeks, depending on which biologic you use. Inhaled anti-TSLP antibodies, so a different route than giving it as an injection, would be attractive to many of our patients. I'm sure we agree. And then this is not a biologic, but this dexprimipexil is actually a non-dopaminergic enantiomer of the primipexil, which is already FDA approved and interestingly was being developed for ALS and found to have significant anti-eosinophilic effects. So this may be something to look for. And then some other targets that are of interest, the OX40, OX40 ligand, sort of the dendritic cell that has a ligand. The OX40 is expressed on the T-cells and can result in increase in tissue eosinophilia and type 2 inflammation. So blocking that may be something to consider. And then also inhaled JAK inhibitors. JAK-STAT pathway has a critical role in signaling of TH2 cytokine-driven immune response. So just things to look out for. So future seems bright. So with that, I will stop. And thank you so much for your attention. And please evaluate this session. Thank you very much, Dr. Khurana. That was fantastic. Now, should I say not-so-bright future for non-T2 asthma before we start the next presentation? Our next speaker is Dr. Praveena Kothota. He's going to be talking on non-T2 asthma. Thanks, Dr. Adrish. And thanks for organizing this session. I have the exact opposite problem as Dr. Khurana about not having too much to say, but maybe not having as much to say. But maybe by the time I finish in 15 minutes, we'll feel a little bit differently. And here are my disclosures, several industry and other relationships. So I'd start by just asking the question, what is non-T2 asthma? How do you define a negative? It's while we are defining something specifically with T2 asthma with biomarkers and potential underpinning mechanism, what non-T2 asthma is is kind of the outside of those lines. It's kind of the blank space in your peripheral vision. So what is it? Is it a lack of T2 biomarkers? Is that what non-T2 asthma is? Is it a distinct set of non-T2 activated pathways? Things I'll show in a subsequent slide, Th17 inflammation, things like new T cell subsets like Th9 cells driving asthma potentially, neutrophilic asthma. What are the distinct set of non-T2 activated pathways? And they don't necessarily fall under a common umbrella like the nice diagram that Sandy showed. So back to that question, how do you define a negative? But we'll do our best. So go back to some basic concepts about phenotypes versus endotypes versus pathways and how non-T2 asthma might fit into these different concepts. So when we think about phenotypes, let me see if the arrow shows. I don't think it does. But I'll use the pointer a little bit. When we think about phenotypes, we think about observable types of asthma, a set of shared observable characteristics and groups of asthma. And those can fall into observable groups that have T2 high biomarkers or T2 low biomarkers. So in the non-T2 space, we see things like obesity related asthma, smoking related asthma that don't necessarily have elevated T2 biomarkers, don't necessarily. But that's not necessarily a mechanistic link between specific non-T2 pathways and those phenotype groups. So now we're starting to have concepts of endotypes where we are moving toward linking mechanistic pathways to those observable clinical features, adding laboratory values to that, maybe adding omics to that, and really having mechanism-defined groups of patients. So we are getting close to that with things like eosinophilic asthma, specific T2 asthmas. But we're not necessarily quite there yet with non-T2 asthma. We have mechanisms. We have groups of observable characteristics. But how those things link together is still an area where we need more exploration. And finally, as I said, pathways. So we are understanding more and more about various immune cells, various T cell subsets that may be driving non-T2 mechanisms. And kind of getting back to more observable characteristics, there are patients who don't have any T2 biomarker elevation, maybe not as many as we think, particularly with repeated measurements. But in this study from the International Severe Asthma Registry, it's about 1,200 patients worldwide. If you take pheno, eosinophils, and IgE, about high 80s, 88% of those patients have some T2 biomarker elevation. But there's about 12% that don't. Does that define non-T2 asthma? Or are we really looking at gradations of T2-ness and non-T2-ness? I think those are things that, again, we need to understand better going forward. And also, in asthma, we're starting to have more of the concept of a treatable trait. And we have T2 treatable traits. We have the presence of eosinophilia in particular that might dictate how we treat somebody, that the presence of eosinophilia might shunt us down toward a specific set of therapies, like increasing inhaled corticosteroids, like specific T2 biologics. We also have pheno, which increasingly we're thinking of as a possible treatable trait as well. But what we don't have is we have things that are not T2 and treatable traits, obesity, things like that, things that we can have lifestyle modifications. But we don't have kind of a mechanistic non-T2 treatable trait. So we're kind of, again, left in this more negative space of what to do with these patients. That's not to say we don't have some potential treatments for non-T2 asthma. Or maybe I should say more appropriately, treatments that are not necessarily T2 targeting in treating patients with asthma. In this piece from Jackie in practice from a couple of years ago, this table basically summarizes the state of the art at that time. We have a couple other things we can think about as well in the experimental space. But we have things like non-pharmacological intervention, smoking cessation, weight loss, which I think we'll increasingly think about as not just lifestyle modification or surgical therapy, but potentially medical therapy now in the age of new weight loss drugs. Bronchial thermoplasty, which is another story in and of itself we can we can talk about offline, but is a non-T2 therapy. And then pharmacologic interventions targeted. And we'll go through a couple of these on subsequent slides. But targeting airway dysbiosis, targeting the microbiome with macrolide therapy, using long-acting muscarinic antagonists. And then I think what's of interest to all of us are things that might be immune targeting, but in a non-T2 way. And some of these are future therapies, not anymore with TSLP. We'll talk about that, whether you think about anti-TSLP as a T2 or a non-T2 drug. Targeting IL-17, targeting IL-6, which we'll talk about in a moment. And then targeting mast cells with CKID inhibitors. So let's go through a couple of those specifically. So this is a well-known story to many of you, using macrolides in asthma in your patients who might be non-T2 or have limited additional treatment options. So this is, again, potentially targeting dysbiosis, which means abnormal microbiome in the airways. The kind of hallmark study, the poster child study for using macrolides in asthma, is this study from Peter Gibson in Lancet from several years ago now called the AMAZES trial, where azithromycin was used versus placebo with exacerbations as a primary endpoint. You can see that the placebo line has a seeper and higher curve of exacerbations compared to azithromycin, almost a halving of exacerbations. And on the graph on the right, what I want to point out here is that this seems to be agnostic of T2 biomarker. The effect seems to be agnostic of T2 biomarker status. Within the limitations of subgroup analysis, you always have to be a little bit judicious with over-interpreting subgroup analysis. But just the top two lines on that table, you can see that there's not much of a difference between non-eosinophilic and eosinophilic patients in the AMAZES trial. So moving on to tezapelumab, this is, I think, an interesting question. Again, we can talk about it. If you come to the, pardon the, not interruption, pardon the intrusion session for copyright reasons in an hour, this might come up. But is TESI a non-T2 therapy? It's kind of maybe, right? This drug shows efficacy in T2 high biomarker subgroups. It does show benefit in non-T2 subgroups as well, though it may be, again, subgroup analysis, you have to be careful to over-interpret. Less so, but statistically significantly on the graphs. Because this is a little busy, I'm going to use the pointer and turn away from the mic just to show you real quick. But if you look, let's say, here at eosinophil cut in a binary fashion with a cut point of 150, you see that both groups, low and high eosinophils, with a pretty low cut point, have statistically significant effects. So you see efficacy with this medication in non-T2 patients. Same if you use pheno. I'll just go to the binary cut point of pheno 25, efficacy in the biomarker high and biomarker low groups. So I think it's reasonable, even though there's an enrichment for response in T2 patients, we can call tezapelimab a non-T2 therapy. Though we can argue back and forth and think, well, does that actually mean there's some T2-ness underlying some of these patients that aren't necessarily reflected in biomarkers? And is this a biomarker problem rather than a difference or a different understanding of mechanism? So moving on briefly to bronchiothermoplasty, I made this pun up about bronchoscopy on the outside looking in. So I think BT has got a lot of good data that many have seen over the years at this meeting and other meetings showing efficacy. And this is definitely not an immunologic-driven therapy. Well, I'll take that back. There are immune changes you can make, with bronchiothermoplasty, but it's not primarily a T2-targeting therapy. And there's some nice data, but we're seeing less of it out there. And that's for various pragmatic logistical reasons. We now have an armamentarium of very effective therapies in the biologic space that are pushing BT potentially to the wayside. I hope that we continue to have it as an option. But if any of you are doing BT in your practices, you'll know that there's less and less support to do so just from a device perspective. But in this study from Jeff Chupp and Mario Castro, they here show improved ventilation pre- and post-BT using CT techniques. And again, there's other data as well showing improved histologic changes pre- and post-BT as well. So this isn't just showing clinical efficacy. It's showing physiologic and histologic efficacy as well. Am I doing OK on time? Three minutes? OK. So a couple other potential therapies that are more in the experimental phase. Imatinib, which is a C-kid inhibitor that we use in hematologic malignancy, does also target mast cells. So this study from Elliot Israel showed in non-T2 patients, blood EOs less than 300 and high BAL neutrophils, an improvement in their bronchial hyper-responsiveness by methicoline. So that's something we're studying in the NHLBI network, which hopefully we'll read out in a couple of years. And IL-6 is also a potential target in severe asthma. This is a little bit of a crossover of things that are in the rheumatologic space versus what's in the asthma space. So in the Severe Asthma Research Program, the SARP investigators found that patients with high IL-6 levels using a cut point of 3.1 had worse history of exacerbation, increased ED visits, and increased hospitalizations compared to low IL-6 patients. And that's independent of their T2 status. So this is a biomarker that acts not in concert with T2-ness, but potentially orthogonally to T2-ness. It gives us something on a different dimension to define risk in asthma. And an IL-6 inhibitor is also being tested in the PRECISE network as well. We have lifestyle interventions as things we can do with these patients. Not to give that short shrift, it's important for us to emphasize these lifestyle interventions with our patients, smoking cessation in particular, reduction in obesity. And again, I think we'll start to see more and more evidence being generated or attempted to be generated for medical therapy for obesity as a potential treatment for non-T2 asthma. So that is my last slide. I'm not going over. So thanks. And I'll also remind everybody to evaluate the session. Okay, so I'm going to pick up from where my colleague stopped. So we already have a patient on our first biologic, so the information that I'll be presenting will be moving on from that point. My name is Mohammad Adrish and I am a professor at Baylor College of Medicine. So I'll be reviewing the prevalence of biologic non-response that we see in real world and as well as in the studies. I'll be discussing some of the selection strategies for the next biologic agents. Again, we don't have any head-to-head trials to say that one is better than the other. So a lot of the data that I'm gonna be presenting today are observational retrospective studies, network meta-analysis where they picked a trial one and trial two and compared them, knowing that the trial one and trial two may have heterogeneous populations. So again, the information that I'm presenting to you, it is not coming from a randomized control trial of drug one versus drug two. And lastly, we will be discussing a suggested protocol that we published with Dr. Hanania maybe last year or year before. So Sandy just presented data from biologics, how we have more and more biologics over the past decade. So back in 2015, omalizumab was still the most common first drug used. And then in 2016, 2017, when we got the approval for NTL5 and NTL4 agents, we started using more and more of the NTL5 and NTL4 agents. And now this is the data from ISAR and clinical study and which shows that almost like 20% at that time was omalizumab back compared to 88%. That was back in 2015. And we are using a lot more mepolizumab, benderlizumab, and duprilumab. So if you're a patient already on biologic, when to decide when the patient is the patient responding? How long should we wait? Gina provides this guidance. It says that if you wanna assess a response in about four months to see whether the patient is responding or no. And if there is unclear response, Gina says that you can go up to six to 12 months to extend the trial and see if the patient is responding, but also address the reasons why the patient is not responding. Oftentimes, we see that the moment they start getting better on their biologics, they stop their steroid inhalers and other controller medications. So you kind of figure out what is going on with these patients and reassess their response. And then if the biologic is actually not working, then you wanna consider switching them. If you look at the UK guidelines, they are a little bit more strict for omalizumab. They say wait for four months before you assess NTI-GE, but for NTI-L5, they kind of don't directly say that wait for 12 months, but they basically say that if you wanna assess responsiveness, that is checked at 12 months. An Australian Center for Excellence kind of put that timeline right around six months or so. So kind of a general time period to be on a biologic and then assess its response is four to six months. And we also have to be mindful that we don't wanna keep our patients with uncontrolled asthma and at risk of exacerbation and all the comorbidities that come with it by waiting too long if one biologic is not working. What is the prevalence of biologic non-response? Again, there's a lot of data out there. I just picked this one, which is from ISAR and Chronicle. This is real-time data. So they looked at patients who are on biologics, up to 23% in ISAR's group, as well as up to 20% or so in the Chronicle were non-responsive for biologics. And so that is kind of what you also expect to see in your practice. About 50 to 60% respond. Another 20 to 30% have less response. And 10% would be like ones who eventually end up getting switched. If you look at the data from the same cohort as to which biologic to use next, it's all over. There are patients who are getting switched from NTI-GE to NTI-L5, NTI-L5 to NTI-L5 receptor antagonist, NTI-L5 to NTI-L4, NTI-L5 to NTI-GE, NTI-GE to NTI-L5. So it's kind of, you know, it's all over. And why it is all over, because when we are assessing patients for switching biologic, there are a lot of factors that we are considering. We are considering what is their phenotype, were they phenotyped correctly in the first place when they were put on biologic. Because a lot of these decisions that are made in real world practices, they are individualized decisions based on your shared discussions with the patient. So a lot of these patients kind of have a different biologic, but there is an increasing trend that you will see in publications that NTI-GE being switched to the next agent, which is because we had 88% of our patients back in 2015 who were on NTI-GE. And as we have more and more biologics in our momentarium, we are trying to see if we can have some of our patients take another biologic agent and get benefit from them. This is data from a retrospective study that was done in Japan. Also looked at patients who were using Omelizumab, Mepelizumab, Benolizumab, and Dopilumab. There are about 100 patients. And what, you know, it's a really busy slide, but really what I want to focus is that, you know, about half of the patients who were on Omelizumab were even less actually continued Omelizumab in this follow-up period. And most of them either switched to Mepelizumab or Benolizumab, or some even switched to Dopilumab. Same thing with Mepelizumab, about 2 thirds continued Mepelizumab and rest of them switched. Benolizumab, same thing, about 15 started with Mepelizumab, out of them about 2 thirds continued, but then a lot of, some of them had to switch. And same thing with Dopilumab. But what I really want to focus is here in this study is that a lot less switched to Omelizumab. You know, similarly, if a patient is on Benolizumab, a lot less number of patients were getting switched back to Mepelizumab. And that kind of goes to the mechanism of actions of this drug. Mepelizumab is basically an anti-IL-5 agent, which is particularly working on eosinophils, whereas with Benolizumab, you can block both eosinophils and basophils, so you have an added advantage of reducing the eosinophil count significantly, especially when you have a patient on Mepelizumab and still struggling with high eosinophil counts. These are some of the studies that are done in like a real world, open label, I'm gonna respect the study. Again, it's a busy slide, but I'll go one by one. So the first one is the Osmo, where they switched from Omelizumab to Mepelizumab. There was about 64% reduction in acute exacerbation, and there was improvement in pre-bronchodile atrophy, one by nine percent. Carpagno, which is the second one, switched Omelizumab to Mepelizumab. This was a retrospective study. There was a reduction seen with exacerbations, improvement of quality of life. There was a reduction in blood eosinophil count and improvement in FE1, and kind of a similar trend in Palea study, which was Omelizumab to Benolizumab, and Kawana study, which was Mepelizumab to Benolizumab. Similarly, more recently, we got data from Brick study, which was converting, where they switched patients with Mepelizumab to Benolizumab, and the Mumler study, where they switched these agents to Dupilumab. What is interesting about the study by Mumler and Higo was that when these patients were switched to Dupilumab, they had elevation in the blood eosinophil count, which just kind of goes to the mechanism of action of how Dupilumab works. It works by keeping the eosinophils in the bloodstream. So that's why we see hyper eosinophilia in these patients, and that's why we sometimes want to be careful using Dupilumab in our patients, where they have really, really high eosinophil counts. Again, as I mentioned earlier, we also have some network meta-analysis and systematic reviews, where they are picking up some of the big randomized control trials and then comparing that information. Again, we are not comparing apples to apples. Each trial has different population demographics. They're studying different patients, so we're not really looking at the same type of, same group of patients. So this was a systematic review of 10 randomized control trials, about 9,000 patients. They're looking at the Sucra score, which is basically looking at the magnitude and the point estimate. Basically, the higher the graph, the better the drug for that particular indication in when we're comparing these trials. So the top one is looking at the exacerbations, prevention, and improvement in FEV1, and asthma quality of life. If you look at the Sucra scores for exacerbation, the Sucra scores were higher for TASI. For FEV1 improvement, it was higher for Dupilumab, and for ACQ, it was higher for mepolizumab in this particular network meta-analysis. There's another one done a year earlier, back in 2022, where they looked at patients with a blood eosinophil count of 150 to 299. Here, the Sucra scores for exacerbation control was higher for Benra and Dupilumab, whereas for FEV1 improvement, it was higher for mepolizumab. Again, data is, you know, you can see the data in all directions. This is another study that was looking at, again, another systematic review, looking at all the different drugs, but I thought this was particularly interesting, where they're looking at the comparative efficacy of tazepilumab and dupilumab, and they compared based on blood eosinophil count and phenol, whether which one of that reduces exacerbation. Again, you can see that the prob, pretty equivalent when it comes to, you know, eosinophil count of more than 150, and across all phenol, you know, levels, but for eosinophil count less than 150, there is a signal that maybe tazepilumab is better. Similarly, for improvement in FEV1, there was no difference. Again, there was all at the same level, so there was no difference in this group. Also, when we're looking at the biologic response, biologic response can also be highly variable. Even if you are switching to a new biologic, you are not guaranteed that you will get a response to that biologic. This was a study, again, by our colleagues in Japan, looking at the switch, and out of the patients who were switched, 10 improved, 24 had no change in their symptom, and actually six of them actually worsened. So again, you may have to then go and do a third switch, or a fourth switch, so be open to identifying these patients who are not responding, and addressing, reassessing these patients, and evaluating their needs for another switch, or another agent. But what is really helpful, that helps, especially, you know, in our practices, that we can look for predictors of good response. What is a specific thing about a patient that I can use to see which drug will work the best? So if you look at the data from different studies, blood eosinophil counts of more than 260, PINO of more than 20, childhood onset of asthma, and allergen-driven symptoms, especially the allergen-driven symptoms, tend to show a better response to the omalizumab. If you look at the data for mepolizumab and Vendra, here, higher blood eosinophil count, patients who have higher number of severe exacerbations in the previous year, and we saw that trend even in the COPD studies for mepolizumab and ventralizumab. Patients with nasal polyposis, patient with oral corticosteroids at baseline, and that's kind of, that was like a primary thing that they looked for in the mepolizumab and ventralizumab study. And patients who have lower FEV1, especially for the ventralizumab, tend to do better. For racelizumab, again, late-onset asthma, patients tend to have better response. For dupilumab, patient with higher eosinophils and higher phenol, particularly higher phenol, because it is targeting IL-13 pathway. And for tezapilumab, which is the newer kid on the block, patients with higher eosinophils, higher phenol, but also patients who have low T2 asthma can have a good response to tezapilumab. What about the dosing frequency? You can use that as a decision, in your decision to start your next biologic. Ventralizumab can be given every eight weeks after the first three months. About the maintenance oral corticosteroid reduction, the strongest evidence is for mepolizumab and ventralizumab, even though when we compared dupilumab also kind of have the same effect, but that is usually our go-to drug if the patient specifically has eosinophilic asthma. There is some data on tezapilumab also, although it is not approved for that particular indication. Some other additional considerations. For melizumab, if the patient has polyposis and chronic urticaria, that might be a drug that would work better. Mepolizumab also had indications for nasal polyposis and hyper eosinophilic syndrome, as well as EGPA. Same thing for ventralizumab. It doesn't have, you know, it has indications for hyper eosinophilic syndrome and EGPA. Dupilumab can also help in nasal polyposis. Actually, kind of, we look at the data, kind of works better compared to the other NTL5 agent when it comes to nasal polyposis and chronic rhinocytis. And also, if the patient has really high pheno, that could be your drug of choice. And finally, tezapilumab can work in both T2 high and T2 low asthma. How long to wait? Proposed washout time is about five to 10 times elimination half-life, so elimination half-life can vary from 15 to 13 days if you look at different biologics. So I'm not gonna wait 300 days or almost a year to switch my patient, keep getting, having exacerbation. Fortunately, we have data from different studies, the OSMO studies, they switched from melizumab to melizumab without a washout period and there was a seamless transition, improving symptoms and no safety concern and similar findings in other real-life study. So we published this a few months ago on kind of some of the pathways that we can follow. What I really wanna focus here is that when you have a patient who's not responding, we wanna know up in four to six months as to how they're doing with the biologic, whether they are improving in their symptom, whether they're reduction in exacerbation, whether there's an improvement in quality of life or improvement in lung function. And if you have a patient who's non-responder, we wanna assess possible causes. Is it because biological dosing is not appropriate? Is it because patient is having circulating antibodies against the biologic? Is it because patient is not taking the biologic or not taking any of his other inhaled controller medication or if the patient was improperly phenotyped? And then we go ahead with reestablishing the phenotype of the patient before selecting the next biologic based on our discussions that we did earlier. So with that, I'll conclude my presentation. So current data on biologic reflects information from real-world studies, systematic reviews and meta-analysis. We don't have information from the head-to-head trials. We wanna timely identify these patients to minimize the risk of uncontrolled asthma. Once we make the decision, we wanna use a personal approach where we identify the phenotype, associated conditions and logistic and regulatory issues that might be specific to your clinic. Maybe your clinic is more tuned to with one particular biologic agent versus the other. And in the end, we wanna make sure we have a shared decision-making with our patient, which is the key to success in most of these situations. Thank you so much for your attention. Thank you. on obese asthma phenotypes. Thank you. Good morning, everyone. Thank you for being here. Thanks for arranging all of this for us, Adrish. Really appreciate it. We're gonna switch gears a little bit and talk about the updates on obese asthma phenotypes, and I'm Deedee Gardner. I'm the Chief Research Officer with the Allergy Asthma Network. The disclosure is that I work for them and that they do receive funding from different grants for different entities, but it has nothing to do with this presentation. I'm gonna talk a little bit about what obesity is, describe the early versus late onset of obesity, and then summarize some of these phenotypes or subtypes that we're seeing. So as we know, obesity is BMI that's greater than 30 kilograms per MTU, and that the rate among adults is increasing over time. We see that more women have a higher prevalence of asthma and obesity, and unfortunately, because of that, they're having worse signs and symptoms, poor asthma control, and then those signs and symptoms really are refractory to standardized medications. Obesity is becoming a public health crisis. So in regards to subtypes, basically this is going to be defined by the characteristics and triggers that are causing the inflammatory processes that we're seeing and how those are responding to therapy. The subgroups are variable between individuals and so that's what makes management of obese patients a little bit difficult. The asthma associated with obesity is either going to be late onset, which we may see, or early onset, and I'll talk about that here in just a minute, where we do have pre-existing symptoms that are aggravated by weight gain. And then we'll look at the heterogeneous of what asthma is. So the SARP, Lester, and U BiPREB studies all looked at different cluster analyses where they identified two subgroups of phenotypes that are inflammatory subtypes, one of those being the ones that are obese asthma with the eosinophilic inflammation that we actually preserve the lung function, and then those that are obese non-type 2 asthma with lower lung function or unpreserved lung function where it's worse. The ADEPT study actually looked at different phenotype studies, four of those phenotypes, which we'll see here in just a second. We are also seeing that eosinophilic inflammation is a big concern with the type 2 obese studies. The non-type 2 are more neutrophilic inflammation with IL-6 levels that are elevated, and again, that lower lung function. On the early onset, this is usually less than 12 years. on what you're using or air Q, have higher symptom scores. They have worse asthma control, unable to manage. They may have a high pheno if that's something that you're using. And then we're seeing that also their airway obstruction is worse. They have hyper-responsiveness, excuse me, and then higher OCS use, and then more ICU admissions in the previous year. So if you're evaluating that, then they have higher risk with this early onset. With late onset, this is usually after 35 years of age, they also have a higher symptom score. Their asthma control is bad, but yet we're seeing the neutrophilic count. We do see that they are also refractory to the inhaled corticosteroids, and so there's little to no eosinophilic inflammation. And so some of this is driven by the airway structure changes and the function that has taken place from that remodeling. So with obesity, we are seeing that, according to these studies that we're seeing up here, that asthma has a role in modulating the inflammatory mechanism. With early onset, there are preexisting symptoms that are aggravated by the weight gain. And so with the extra adipose tissues that are on the thorax, that is causing the airways to... So this was modified with. asthma, you do see that we have two types of late stage, one of those looking at the greater than 12 years old, more prominent in females, non-atopic, the eosinophilic inflammation, the preserved lung function, and then frequent exacerbations. However, there's a second subset where we're looking at the late onset with, again, prominent females, non-atopic, but the neutrophilic inflammation. So there's a separation with lower lung function and then the elevated. The early onset, what we've also seen, is that the patients are having three times more increase in hospitalizations, six times more increase in ICU admissions, and then they seem to have continuous or consistent wheezing or consistent symptoms. The mechanical effects that we're seeing because of obesity are usually associated with the early onset of obesity, so the younger than 12, but again, that excess fat that is around the trunk is causing a reduction in the amount of lung volumes that the patient is able to, and they're having worse breathing issues. So the airway responsiveness is causing the greater collapsibility of the small airways. Ideally, weight loss would be the answer, but as others had mentioned earlier, that with weight loss, we're either seeing surgery or other medications that can be utilized to be the answer here. For the inflammatory changes, we do see that the adipose tissues themselves are immunologic active organs, so that contributes to the systemic inflammation that is taking place in the body. Those adipocytes are actually participating in the secretion of immune mediators, so those adipose cells are actually causing more issue that are taking place with these patients that have obese asthma. We do know that obese asthma, many patients do have comorbidities, whether that be a metabolic syndrome, they're having diabetes, they may have hypertension, OSA, GERD, or depression. So each of these comorbidities needs to have its own treatment, and so we do need a multidisciplinary team to take care of these patients in the long run. Also, in regards to depression, having some type of modifiable treatment, rather that possibly studies are demonstrating that there is effect with meditation, and other ways outside of medication to assist with these patients. So with metabolic diet and nutrition, again, obesity is tied usually to diet, but we're also seeing the genomic aspect. But when we think about metabolic diet and nutrition, we do know that the gut biome does change with obesity, and so it becomes a little more, has more osmolality, excuse me, with that. So there's more inflammatory process taking place. The largins actually, and there is an increased, reduction in largins and increase in ADMA levels, and so nitric oxide is actually inhibited from being produced, and so that's why you may see a lower overall at the end of the day apheno. Diet may actually help improve this situation with many of these patients, but again, you may actually need to come up with some other alternatives. So the biomarkers, we've heard much about those. The biomarkers with obesity, unfortunately, many of these are predicting the exact sorbations. They are successful with therapeutic response, and the risk of lung function decline, which is great, but many times with this type of asthma, these biomarkers are not as sufficient or efficient. So we're finding that they have a poor predictive value in obese patients, that there's, because there's a unique inflammatory process taking place because of the adipose tissue, the gut biome, and how that is working, and then also, we need to identify new biomarkers specifically for obese asthma. The management signs and symptoms for asthma that is related to obesity are different to some extent than what we're looking at our traditional asthma management. So diagnostic challenges are huge in the pulmonary function lab. Many times we have a difficult time with our body boxes, trying to arrange for patients to be in, depending on how large they are. In regards to treatment, again, those treatments need to be more specific. When I'm thinking about treatment from a public health perspective, I'm looking at where are we seeing the higher prevalence of asthma and obesity, and so you can see here that you're seeing more obesity within the states that are darker blue than anywhere else across the country. So, excuse me. So, in summary, obesity, asthma is extremely complex. Again, it's usually in women. Later onset, it's difficult to treat. They have a very poor quality of life. We do see that there's early versus late onset, and we showed that previously. The biomarkers and therapeutic approaches need to be more specific to these types of patients, and then we do need to include patients in the studies from the get-go. Thank you very much. Thank you.

type 2 asthma

non-type 2 asthma

obese asthma

type 2 inflammation

biomarkers

biologic treatments

macrolides

multidisciplinary approach

specific treatments