So, I would like to thank the organizers for the opportunity to speak today. And thank you to all of you for staying on Wednesday afternoon and for being part of this session. It is a really exciting opportunity for me and my co-chair as well as the other speakers to be able to speak on this topic today. So, the goal of today, this afternoon's session, is really to talk about non-TH2 asthma, looking at novel mechanisms and biologic mechanisms underlying non-T2 inflammation, and how, you know, these biologic signatures are really informing future therapeutics. The objectives of today's symposium is really to understand the prevalence and outcomes associated with non-T2 asthma, where I'll discuss the pathogenesis and novel contributors to the development of non-T2 inflammation. We'll discuss current therapies for patients with non-T2 asthma, and then finally, we'll discuss kind of new therapeutic targets for this patient population. I have the privilege of being with Dr. Deepa Rastogi, who's going to speak to us today on metabolic dysregulation and obesity and non-T2 asthma. We're going to change the format, the schedule, just a little bit, and she will be followed by Dr. Akuthata, who will be speaking about non-T2 asthma and covering novel mechanisms, and we'll end with Dr. Andy Hudler, who will be speaking about emerging therapies for non-T2 patients. So, I have no conflicts to disclose. So, it is no surprise to anyone in this room that, you know, asthma is a really common chronic respiratory disease. It's a heterogeneous disease that's characterized by chronic airway inflammation, and it's really defined by its respiratory symptoms. These are things like wheeze, chest tightness, and shortness of breath that are really variable over time and intensity. It's associated with variable airflow obstruction and is at least partially reversible with bronchodilator use. Chronic pathobiology is really very nicely illustrated here on this beautiful illustration from John Fahey and colleagues, and what you can see is that the kind of underlying pathology of the disease is quite evident here. What you will see is you have basement membrane thickening, you get chronic airway inflammation, you get subepithelial fibrosis, as well as increased submucosal glands associated with increased butum production. One of the things that we've come to recognize, however, is that there is a variety, there's a notable heterogeneity in the presentation of the disease, and this was really nicely illustrated by this beautiful work from Wendy Moore and colleagues using the Severe Asthma Research Program data, where they used clinical variables to identify subgroupings of individuals with asthma using three characteristics, that's baseline FEV1, maximum FEV1, and age of onset of the disease. And they identified five clusters of individuals that had asthma. And what's notable about these clusters that were identified is that you had a combination of individuals that had early onset disease, this was really characterized by high markers of T2 inflammation, individuals had elevated sputum eosinophils, and the most severe of those categories was associated with fixed air flow obstruction, and these were older individuals who had late onset disease. Notably, they also had increased eosinophils, but they were noted to be less responsive to inhaled corticosteroids. So the question really is, what is the underlying biology that's really driving these kind of clusters of endotypes that we see in asthma? Now I'm going to make this obviously much more simplistic than the underlying immunology is, but what we have come to recognize is that there's kind of two flavors of asthma. You think about it in the context of allergy-specific or allergic airway inflammation. These are individuals that have allergic eosinophilic inflammation, and this is really characterized by aeroallergen exposure and then polarization of naive T cells into TH2 polarization. These TH2 lymphocytes then go on to secrete a variety of different TH2 cytokines. These are things like IL-4, IL-5, and IL-13 that all increase allergic airway inflammation. Notably, other kind of environmental perturbations, things like smoke exposure and other microbial signatures that can actually influence non-T2 polarization, and this is really characterized by IL-C2 cells. These IL-C2 cells, when they're activated by TSLP, can go on to secrete a variety of different cytokines, again, including IL-5 and IL-13 with much less IL-4 regulation, and this is really associated with non-allergic eosinophilic inflammation. The reason these paradigms are really important is because, as you all know, we have novel biologic therapies that can be targeted for T2 asthmatics. So as you know, there's a variety of different biologic agents that have been highlighted throughout the course of the CHESS conference in 2022, including dupilumab, which targets the IL-4 receptor and this pathway in terms of allergic eosinophilic inflammation, and we have metbolizumab and benrolizumab that target the IL-5 and IL-5 receptor. These medications have really revolutionized our ability to take care of individuals that have TH2 inflammation, but what about the 50% of individuals that have non-T2 asthma? And this is kind of the feature or the focus of today's talks. So what do we know about non-T2 inflammation? In some beautiful work by Prescott Woodruff and colleagues using transcriptomics of the airway epithelium, they identified a kind of a signature of T2 gene expression. These are things like periostin, CLCA1, and SerpinB2, and what they identified is really two clusters of patients that have underlying airway inflammation. One is a cluster one, which is the TH2 high expressors, and then a very large proportion of individuals who sit in this non-T2 paradigm. So these are low expressors of these genes. What's notable is for a variety of different outcomes, there is a difference between T2 high and T2 low asthmatics. In these examples that I show in the lower quadrant here, one of the things that you'll see is the T2 asthmatics are associated with kind of poor asthma outcomes. As you can see, they have increased MUC5AC and MUC5B ratios. This is just an indicator of increased airway inflammation in sputum production. They have increased reticular basement membrane thickening, and they also have increased BAL, eosinophilia. But what about the underlying asthmatic airway in individuals that have non-T2 asthma? What can be associated with poor outcomes in those individuals? In some work by Quao and colleagues, they did molecular phenotypes of asthma using induced sputum. This is, again, looking at 140 asthmatics and non-asthmatic controls. One of the things that they identified using induced sputum transcriptomics is that there were three characterizations, or three different clusters of individuals. There's one cluster that is associated with eosinophilic inflammation, and then two clusters that were identified that were associated with non-T2 asthma. What's notable about these two endotypes that were associated with non-T2 asthma is that it was in the green cluster, these were individuals that had interferon signaling abnormalities, and then in the blue is characterized by mitochondrial dysfunction. These two categories are really kind of the basis of some of the discussion that we're going to have today, because some of these are also kind of novel areas for targeting for therapies in the future. So one of the things that the goal of today is really to think about how we might think of this as a paradigm shift and really understanding non-T2 asthma and its pathogenesis. In addition to incorporating a variety of different environmental exposures, like we talked about, the pathogen, the microbes, as well as a variety of other environmental perturbations, if we can use the combination of transcriptomics and genetics, as well as airway physiology, including lung function measures and airway histology, as well as other microbial signatures in the microbiome, that we can actually identify the underlying biologic basis of T2 asthma and really identify some additional therapeutic targets for these individuals. So the conclusions of today is really that non-T2 asthmatics make up about 50 percent of the asthma populations, but our treatments to date are really relatively minimal in terms of what we have for these individuals. Th1 inflammatory pathways are associated with poor asthma outcomes, but they're really not really well understood in terms of identifying potential targets for these pathways in terms of the inflammatory pathways. And I think an improved understanding of how non-T2 asthma impacts asthma susceptibility and disease severity will be essential to identify novel targets for therapy for these patients. And so the goal of today's symposium is really to highlight some of the kind of novel underlying biology that we're starting to identify and really talk about the potential new therapies and targets for this really important patient population. And so I am going to now, if I can, invite up my colleague, Dr. Deepa Rastogi, who's here from George Washington University and the National Children's Hospital in Washington, D.C., who's going to talk to us about metabolic dysregulation and obesity with asthma. Thank you so much. So actually, we do have a few minutes if you want to come up and ask Dr. Sharma some questions right now, or we're happy to take questions later at the end. Yeah? Yeah? OK. All right, good afternoon, everyone, again. And for my talk, I'll be focusing on the contribution of obesity and metabolic dysregulation as being a sort of large subset of non-T2 asthma, and just walk you through some of the recent studies that highlight how this may be contributing to this particular subset of asthma. So I have no disclosures. Through the talk, we'll first discuss the association of obesity with asthma, and then move on to distinguishing the role of metabolic dysregulation with a focus on insulin resistance and dyslipidemia. Nothing about obesity is simple, so we'll talk a little bit about the interplay of metabolic dysregulation with other obesity-related complications, and finally, the effectiveness of some off-the-beaten-path medications from the asthma perspective, but well-established from the perspective of management of metabolic dysregulation and how they may be effective in asthma. So starting off with the association of obesity with asthma, again, I'm probably preaching to the choir here. You've all stood out and stayed this long, so clearly you're interested in this. But we all know that the proportion of individuals with asthma who carry the comorbid condition of obesity is substantially higher. This is data from CDC, where if you were to look at this map on the right, you can pretty much overlap the burden of obesity in the country with the burden of obesity-related asthma, such that about one and a half times as many individuals with asthma carry the burden of obesity as compared to those who do not have asthma. While we don't have such pretty pictures for children because we always lag behind in pediatrics, this was a seminal study that was run by Dr. Lang, where he took data from about a network of 10 pediatric emergency department sites and essentially could identify a higher risk of about 25% as a relative risk of 1.25, of 25% new cases in children who are obese, and about a 30% higher asthma risk in obese children as compared to, excuse me, such that we're looking at about a million preventable asthma cases. So now those of you who work with children or deal with the sequel of asthma that started in childhood, you know that we really have no window in what we understand of asthma to truly prevent asthma. So the way I look at it is if we can identify children who are obese and are at risk to develop asthma, then maybe we truly have a window to execute primary prevention in the context of asthma. So this is particularly interesting for me as a pediatric lung specialist. So this is a figure that you just saw in Dr. Sharma's presentation, but I'll draw your attention to cluster three, which is where in this excellent study led by Dr. Moore, they landed up identifying a subset of individuals with asthma. And in this cluster, the individuals had highest BMI. They had the lowest prevalence of atopic sensitization as measured by skin prick test positivity. They had the lowest IGE, total IGE. And yet when we looked at their asthma disease burden as the number of oral corticosteroids used, 61% had used more than three oral corticosteroids in the duration. I think it was an annual use of oral corticosteroids, along with high coexistence of morbidity such as G reflux disease and hypertension. But quickly identifying that what is happening in adults may not directly extend to children, the same group, the Severe Asthma Research Program, extended this profile towards children and did not find the same distinguishing features. So clearly there are some differences between children and adults. But we'll be going over some areas that overlap in children and obviously we'll identify those that are distinguishing features. So building on the story of the link between obesity and asthma, the most common measure we use is body mass index, which has been maligned extensively because we all recognize that it's not the best way to measure adiposity. But even so, the early literature that supported obesity and asthma links looked at BMI and found higher relative risk, particularly among individuals who were non-atopic. The same findings were mirrored in the pediatric population, where in the bottom graph you can see the bar that is turquoise are children who are morbidly obese. And consistently, whether we look across boys versus girls or we look at different ages, kindergartners, second graders, or fifth graders, the turquoise bar is the highest, suggesting that morbid obesity is associated with high asthma prevalence in children as well. But then distinguishing what about obesity sets the stage for asthma, in this study they went on to further separate out individuals who had high BMI and were either not abdominally obese or did not have truncal adiposity or have truncal adiposity. And as you can see within what's in the red box, that the odds of having asthma were particularly higher amongst those that were obese with excess truncal adipose tissue. But we all know that all individuals who are obese do not develop asthma. So what else about obesity could be distinguishing? And that's where metabolic dysregulation comes in. So in this study that is on the left-hand side, again, you can see that we are looking at obesity in the form of BMI. So what's lean is in blue, overweight is in red, and obese is in green. But then in this study, they went on to look at their insulin resistance measured by homeostatic measurement of insulin resistance, HOMA-IR, and divided it in tertiles because we still do not have sort of a normal HOMA level for adults or children. And as the tertiles went up, particularly individuals that were obese and had higher insulin resistance had higher odds of asthma, suggesting that there was possibly either an interaction or an additive effect of metabolic dysregulation with body fat. And a more recent study that was just published, again, out of the Severe Asthma Research Program, they again identified not only increase in the odds of asthma because, again, a lot of naysayers will say, hey, they just might be deconditioned if they are obese. Looking at lung function, they demonstrated nicely a decline or a lower level of both post-bronchodilator FEV1 as well as FEC in individuals with higher categories of HOMA-IR. And that relationship, again, was more evident amongst those that were morbidly obese when they subsetted the data looking at those with BMI greater than 40. Bringing in the story of dyslipidemia, on the left-hand side, HDL is your good lipid. So consistently, HDL is associated with a protective effect against asthma, irrespective of the BMI that the individuals fell in. But the story with triglyceride is less clean, where particularly among individuals who may be in the lower BMI category but have high triglycerides are at risk of having higher odds of asthma. So this is an intriguing finding, an epidemiological study, which obviously needs validation and a better understanding through mechanistic studies. And then bringing the two together, triglyceride glucose index, which brings in, again, the triglycerides and glucose, so insulin resistance with dyslipidemia. In this recent study, they went on to look at respiratory symptoms, again identified a significant contribution of triglyceride glucose index in its association with symptoms associated with asthma, with chronic lung disease. So they had incorporated other chronic lung diseases as well, where asthma and chronic bronchitis, but less so emphysema, were associated with this. And then interestingly, again, highlighting the differences in different studies, they found a greater association of triglyceride glucose index with a restrictive lung disease pattern as compared to an obstructive pattern. Extending this into the pediatric population, in the same population that I showed you those turquoise bar graphs, they went on to quantify insulin resistance as acanthosis nigricans, the black discoloration on the base of the neck. And children who carried a diagnosis of asthma had higher prevalence of acanthosis nigricans as compared to children without asthma. Looking at dyslipidemia, again, children with asthma were the ones who had greater evidence of dyslipidemia, particularly when quantified with lower HDL. So patterns that we are observing in adults are present in children as well. And longitudinal studies have gone on to show that these may start really early. So having spoken about the early-onset asthma, those children who may be set up to develop obesity-related asthma early may actually be set up for worse of lung function as well as disease burden as obese adults. And finally, looking at the interplay of metabolic dysregulation with other obesity-related complications. In this study by Forno et al., they brought in the interaction between HOMA-IR, the measure of insulin resistance, and BMI. So what is marked in blue are children who had varying BMI z-scores. So as you move further out, the higher the z-score, the greater the obesity. So clearly, higher BMI is associated with lower lung function as well. But when you factor in insulin resistance, the drop in lung function as body mass index goes up is significantly higher. So again, an interaction between body weight and metabolic dysregulation. And in the adult world, they looked at the interaction between BMI and insulin resistance and identified a point estimate of 1.23, suggesting 23% higher risk. When they factored in triglycerides in the same model, it did not substantially change. But I'd like to draw your attention to the adjustment for CRP. So now we are looking at obesity, metabolic dysregulation, and inflammation. So with addition of CRP, you have about an 8% greater risk explained by inflammation. So you can imagine those individuals who have greater truncal adiposity, particularly associated with the inflammation, as well as with metabolic dysregulation, are at substantially higher risk, about 30% higher risk of having asthma-related disease burden. And similarly, in the pediatric population, we have linked T helper 1 to T helper 2 cell ratios. So greater Th1 polarization or non-atopic inflammation with both insulin resistance and with HDL, again, inverse correlation with HDL, that being the good lipid. So then we landed up doing a similar modeling approach as the other study that I just showed you. So what is in the unadjusted analysis is the association of the inflammatory responses with each of these lung function parameters. And what is adjusted is adjusted for the insulin resistance values in these children. So residual volume, for instance, you'll see a beta of negative 8.56. When we adjusted for insulin resistance, it dropped to 7.03, suggesting part of the association of non-atopic inflammation with lung function is being mediated by the metabolic dysregulation. And you can see pretty much for three lung function parameters, we see a mediating effect of insulin resistance, again, suggesting two complications of obesity, inflammation and metabolic dysregulation may come together to give a rise to worse of lung function. And lastly, what can we do about these, particularly in children where we don't have a lot of luxury to do calorie restriction because we have to obviously monitor their somatic growth? This was a study where we brought in carotenoids, which is your objective measure of fruit and vegetable intake. And what I'd like to draw your attention to is the inverse association between total carotenoids and insulin resistance and its protective effect on HDL. So something as simple as diet modification, if it can be called simple, may land up indeed altering or modifying these metabolic abnormalities that we have discussed today and may contribute to decrease in the disease burden in our obese children with asthma. So lastly, to talk about the effectiveness of some existent medications that are well established for metabolic dysregulation and how they are being found to be effective in asthma as well. So on the left-hand side, I shared with you a paper which they looked at the impact of metformin initiation on cumulative incidence of emergency department as well as hospitalization for asthma. So the solid line are basically individuals who were matched for those that were started on metformin but were not started on metformin. So that's your control. And that's the increase in the cumulative ED visits over the years that they were followed. And individuals who were started on metformin, as you can see, clearly had fewer ED visits. But what was really remarkable was the decrease in the hospitalization frequency in these individuals suggesting that metformin may somehow, if we don't understand the mechanism, work in decreasing the asthma disease burden. When we look at the role of statins, so looking at the modulating effect of dyslipidemia, the way this is set up on the right-hand side in these forest plots, when you have the data distributed on the right side, it favors statins. And on the left side, it favors placebos. Looking at the impact of statins on the asthma control test on pre-bronchodilator FEV1 and post-bronchodilator FEV1, just highlighting that the impact of statins is particularly notable and significant in the context of asthma control test with a less clean story when we look at lung function. So how are they, again, modulating and decreasing the disease burden needs to be still investigated. And it does not appear to be just through their effect on lung function. So bringing this all together, the data I've shared with you today suggests that obesity is indeed associated with asthma. Body fat distribution does matter, so maybe we can identify those who may be either on the higher spectrum of BMI or even in the normal range, but may be obese or adipose from the truncal perspective, which comes hand-in-hand with metabolic dysregulation. Both insulin resistance and dyslipidemia are associated with asthma, and one of the mechanisms may indeed be through their effect on lung function. Obesity-mediated immune responses and nutritional deficiencies also travel with metabolic dysregulation. So again, whether we treat metabolic dysregulation and improve these, or we improve the immune responses and nutritional deficiencies and improve metabolic dysregulation, but that appears to be a different approach than what we have thus far to manage our individuals with asthma. And current existent medications against insulin resistance and dyslipidemia appear to be effective against asthma, but we don't really fully understand how. So I'd like to thank you for your time, and do evaluate. We have time for a question or two, if anybody has one. Thanks for the presentation, I really enjoyed it. I'm Hei-Yu Li, I'm from Monticello Medical Center in the Bronx, New York. My question is, as we all know, there is no gold standard for diagnosing asthma, and in a clinic setting, we see very often we have a morbidly obese patient coming to us. They could have reduction in their FEV1 and FDC on the PFT simply from the obesity without actually asthma. And of course, they usually have subjective symptoms, shortness of breath, poor exercise tolerance. My question is, were this population excluded from those studies that looked into the relationship between metabolism, lipids, whatnot, and asthma? And if this population was somehow looked at in those studies, would that make the interpretation of those studies difficult for the clinicians? Thank you. No, that's a very valid question, and thank you for bringing that up. And it is indeed that interplay of obesity and its effect on lung disease which makes it difficult, but so much of asthma is difficult for that exact same reason and the heterogeneity that we're identifying. So the way I think about it is as we have better biomarkers, then maybe this subset, whether we call it just the effect of obesity on lung function, or we call it obesity-related lung disease, or airflow obstruction, or the terminology one can discuss extensively. But whatever the impact of obesity is on the lung needs to be defined better. So yes, they were not excluded from these studies. They're all comers that they had looked at and could define this association. But absolutely, that's where we need to go. Because what I keep thinking about is the fact that there are those that are obese and may not have influence on their lung function. So what distinguishes an obese individual from impacting their lung versus not? I might actually ask one question as well. I was just curious about the GLP-1 inhibitors really have been impressive in terms of their improvements in insulin control, or glucose control, sorry, and have had impacts on weight reduction in obese individuals. So I'm just curious, are we looking at that in the context of asthma? And is there any association with improvement in asthma outcomes in these non-T2 individuals? Thank you for bringing that up. And I was debating about that data when I was putting my talk together. How much do you keep, and how much do you take out? But there is actually an excellent paper that was published, I want to say, last June. Katie Cahill, I would recommend you all to look into her work. She's really an up-and-coming star in this field where she indeed published on a very large set identifying a substantial beneficial effect of GLP-1. But again, as you said, it affects your metabolic profile as well as causing weight loss. So it will be so interesting to see whether we compare it to patients who have had bariatric surgery, and Dr. Dixon way back had shown the benefit of bariatric surgery. I think they're so interrelated. I don't know if we'll be able to distinguish each aspect. And again, there's only so much of the mouse models that you can extend into human data. But they all, I think, go hand-in-hand, and they just worsen. But distinguishing those that may have one or the other and how that influences lung function will be important. There we go. So we'll be building to that. I know you had a question as well. How do we have time? I don't know what to do with the record of my results. So I have been receiving a lot of patients with mild elevation of ESR-CRP. And I have been looking for an answer, because there were a lot. And I figured about this chronic inflammatory state condition, and there was something common between all, and it was obesity. Do you think this chronic inflammatory state, which they recently, as I found, they say, if obesity causes chronic inflammatory state, which is actually the main, like, other cause of cardiovascular disease in this population. So what you are mentioning in this as a cause of non-T2 asthma, do you think it's that chronic inflammatory state exactly? And do you think it actually is in correlation with increased cardiovascular conditions, regardless of cholesterol level or others? I'm a bit fish out of water, because I am a pediatrician. So my patients don't come in with coexistent morbidities like these ones. But it's a very valid point. I think what we'll hone in on is a common immune response. And I just think we've explored that better, defined it better in the cardiovascular world. And as I see this field moving, we will be distinguishing exactly what component of immune dysregulation is contributing to cardiovascular disease versus pulmonary disease. A lot of the immune profiles we are identifying are identical, with adipose tissue inflammation being sort of the perpetrator, and that's where it begins. So there's a fair bit of work coming out on macrophages now. We've defined what it does to the coronary arteries. We are just beginning to define it in the pulmonary context. But you're absolutely right in there being overlap. Again, I can't imagine that it's complete overlap. So getting those distinguishing features will help us guide our therapy better. And ESR and CRP, I think they're so non-descriptive in our ability to define that kind of detail. So the sooner we move towards whether it's eosinophilic, non-eosinophilic, we get Th2, T helper cells in our routine gamut. It's been in research for the longest. But we clearly need to bring it into the clinical realm of identifying and quantifying these measures better. I don't want to hoard it. So thank you all. And I'd like to invite Dr. Akuthutta to come up and give the talk. Thank you. Thanks, Sunita. Thanks, Deepa, for organizing this. And thank you all for being troopers and being here on the last day. That is incredibly impressive. So I'm going to talk a little bit about mechanism in non-T2 asthma, maybe go slightly counter to a couple of things in the prior talks, but not completely. I'm Praveen Akuthutta from UCSD. I will point out that I have a few disclosures, mostly unrelated to this talk, but several industry relationships with research funding and some consulting as well. So when thinking about what is non-T2 asthma, I like this figure maybe as my favorite figure that's been in the literature over the last several years. This comes from Mark Gauthier and Sally Wenzel at Pitt. And the reason I like this figure is because it speaks to the complexity of mechanism in asthma. It talks about a spectrum, or it implies a spectrum of T2-ness, T2 high, type 2 high to type 2 low, and this kind of gradient color. And I like that because I don't necessarily like thinking about the concept of type 2 asthma as a categorical variable. I think thinking about it as a continuous variable with other potential non-type 2 etiologies or non-type 2 drivers kind of under that or concurrent with that, I think that's probably, to me, the best mental heuristic for thinking about type 2 versus non-type 2 asthma. And actually, even more fairly, I would actually maybe make the, I don't know if that came up at all, but I'd make the red part, the type 2 high part, maybe take up more of the bar in the spectrum of what constitutes type 2 versus non-type 2 asthma. I think there are people who have, many, many, many patients who have at least some expression of type 2-ness, but who have some other non-type 2 mechanisms that can be potentially targeted. And some of those are implied in the figure as well, including the presence of neutrophils, some patients who are posigranulocytic, some patients who have other T helper subsets beside T helper type 2 subset, which are contributing to pathogenesis in asthma, including type 2, type 1 high patients, TH17 high patients as well, obesity-related factors, which you just heard about, which may include also IL-6, which I'll talk about in a few slides as well. So I think rather than, again, just to reiterate, I think thinking about type 2 versus non-type 2 asthma is probably best served by not thinking of it as an either-or proposition. So, and I'll kind of expand on that a little bit here. So there is some data from the International Severe Asthma Registry, which is, as the name implies, an International Severe Asthma Registry from several countries around the world. And this paper in Jackie in practice from last year describes the pattern of type 2 biomarker elevation in patients in the registry, whether they have high eosinophils, high IgE, exhaled nitric oxide, and what combination they have those elevated type 2 biomarkers. And I think what's most interesting about this paper is that only 12% in this Venn diagram fall outside the three circles of elevated biomarkers. So the patients who have absolutely no expression of type 2-ness is probably relatively small. This paper was presented in the best of chess session on Sunday by Professor David Price from Singapore. Seems like a long time ago now on Sunday, doesn't it? But Professor Price presented this paper also from the International Severe Asthma Registry. And I won't go through all of the gory details of the paper, but the paper differentiates through a kind of flow chart who is likely to be an eosinophilic patient versus who's not likely to be an eosinophilic patient. And eosinophilic is not the exact same thing as expressing type 2-ness as a whole, but we'll just use that as a proxy. And in this paper, only about 1.6% of the patients in this paper were graded as truly non-eosinophilic. And even within those non-eosinophilic patients, some of those patients even had some expression of type 2-ness, whether it be some concurrent eczema in those patients. Those patients were also more likely to be on anti-IgE therapy. They were more likely to be on leukotriene modifiers as well. So again, even within patients who maybe would be labeled as non-type 2, there is some type 2-ness there. But the flip side of that is that in many of these type 2 patients, they likely have non-type 2 inflammatory pathways contributing to their airways disease. And just to hammer this point home a little bit more, when you look at some of the data that we quote a lot, even for type 2 biologics, this is the Serocco trial from Gene Bleeker. That was one of the two pivotal phase 3 trials for benrolizumab. And we all now think, when we're in clinic seeing our patients, we think pretty concretely. I'm as guilty as anybody of being very concrete with my thinking when I'm in clinic versus being a little bit more maybe imaginative and less concrete when I'm outside of a clinic about we're forced to make binary decisions in clinic. But in this paper, the patients above 300 eosinophils did indeed respond well to eosinophil depleting therapy with benrolizumab. But it's not a complete reduction. So there are many patients who are biomarker positive who don't respond to type 2 biologics. So that implies potentially alternative mechanisms, non-type 2 mechanisms that might be underlying. And the converse is true. So even though we cannot prescribe a biologic or a type 2 biologic, for the most part, for a patient who's biomarker negative, the SIRECO trial is another good example. In the panel on the right, patients with eosinophil counts less than 300. There was plenty of responders in that group as well. So both sides of the coin tell us that type 2-ness is not binary, that our biomarkers are imperfect. And we need to probably think of it a little bit more of a vanilla ice cream with a bunch of mix-ins in it rather than either one flavor or another. Hopefully, that analogy was not too strange. You can tell me offline after the talk. Or don't. I'll just believe it was fine. So getting to potential non-type 2 pathways, this figure is similar but a little different from what Sunita showed earlier. So I think this figure is illustrative of not just what can happen. Sorry, I'm having a little, maybe I'll use the trackpad instead. Not just what the important cardinal players are in type 2 mechanisms, but non-type 2 mechanisms as well and how they might interplay with each other. And I want to point out a few key things here. And tell me if I'm going along, OK? There are important contributions, both upstream from canonical type 2 and type 2 low pathways that are from epithelial-derived cytokines. You'll hear from Dr. Hudler a little bit about TSLP as well. But these are so-called alarmins that act directly on dendritic cells, in which we think of potentially priming type 2 responses. But what I'd also like to point out is that dendritic cell, naive T cell interaction can potentially be upstream of other T cell subset activation, whether it be things that might be protective in asthma, like T regulatory cell activation, but things that are potentially pathologic players, like Th17 pathways and Th1 activation as well. And then you can see on this T2 low or non-type 2 side of the figure the presence of neutrophils, which are also likely important in some patients with asthma, particularly ones who are refractory to our usual therapies. But I also want to start back on the type 2 side of the figure with another cellular player, the mast cell. So even though we think about mast cells as being part of T2 pathways, I do want to talk about it here in a non-type 2 mechanism talk. Because I think this is one area where we might see some movement and potentially some movement in patients who are biomarker negative as a potential target. So one way to target mast cells is through C-kit inhibition. So we think about using mastinib and imatinib in patients with hematologic malignancies. But these are also potentially ways to target mast cells. And one paper in particular that you may have seen from a few years ago, also by Katie Cahill and Elliot Israel, looks at using imatinib to specifically target mast cells. And in this pilot study, this was indeed an effective strategy in improving bronchoreactivity by methicoline challenge. And what's interesting and why I include this in a non-T2 talk, even though, again, we usually don't think about mast cells as a non-T2 target or as a non-T2 cell, the responders to imatinib were more likely to be neutrophil high. And they were also more likely to have low blood eosinophils. So again, I also use this to challenge our dichotomization of T2, non-T2 when we're thinking about asthma. And then also shifting to other potential targets as well. This is relevant to Deepa's talk. IL-6 is sometimes seen in these patients, is often seen concurrently as a co-traveler with metabolic syndrome. People with elevated CRP, elevated ESR also have elevated IL-6. This paper is from the Severe Asthma Research Program from Michael Peters and John Fahy. And what they showed in this paper from a few years ago is that patients were more likely, if they're IL-6 high in the Severe Asthma Research Program cohort, to have exacerbations within the last year, have ER visits within the last year, and or be hospitalized within the last year. And they also showed that in their local cohort in San Francisco. And what's key about this is the IL-6-ness in predicting somebody's exacerbations and hospitalizations was independent of their T2-ness. So this is not something, you know, you can find plenty of literature out there of other T2 biomarkers that track very closely with T2-ness, but this is independent of T2-ness. And so this gives us yet another potential therapeutic target. So things that we would normally think about in rheumatologic disease, inflammatory arthritis, now we can think about these kind of targets potentially in asthma, or at least some patients with non-T2 asthma. So, and then finally, and this is obviously not a comprehensive talk about the potential targets one might be able to go after in non-T2 mechanisms, but there are alarmants now as well, not just tezepilimab or anti-TSLP, but anti-IL-33 strategies that are coming down the pipeline as well. And, you know, I include this here, and again, Dr. Hudler will talk about this some more, because dendritic cells are, you know, we think about these canonically as interacting with naive T cells to prime type 2 pathways, but other T cell subsets, you know, being primed by DC interactions with naive T cells are also important to think about and potentially relevant. And I won't talk in too much detail here, but, you know, this again gets to my point about heterogeneity between type 2-ness and non-type 2-ness in individuals. You know, we've been thinking about in the asthma community tezepilimab as a non-type 2 therapy, because it's effective in the biomarker low patients, but in the biomarker high patients, it's just as effective with the low rate ratio for exacerbation, if not even more effective than in the non-type 2 patients. So, again, an argument to think about these things more as layered pathways rather than things that are distinct from one another. And, you know, along this idea of disrupting or modifying antigen-presenting cell, dendritic cell, T cell interactions, one other strategy that's down the pipeline that I've been involved with, you know, with Sanofi is a OX40 ligand monoclonal antibody, which you could think about as potentially disrupting multiple other T cell subset activations as well. So these are all, you know, potential ways, and there's many more that one could think about as well. And these are being targeted in clinical trials as well. In one network that I'm involved in, the NHLBI PRECISE network, which is testing multiple interventions on an adaptive platform design, we are indeed doing a larger phase 2 study of imatinib and also testing anti-IL-6 therapy as well, and people who have, you know, low type 2 biomarkers or high IL-6. So I'll just end with that, that hopefully more to follow as you come to meetings over the next year, two years, three years, five years, we'll have more options potentially for non-type 2 pathways, but we shouldn't necessarily think of them as distinct, but potentially overlying expressions of type 2-ness. And if anybody lives in any city where you're near one of the PRECISE sites, got the QR code up here, Dr. Hudler will have it up as, or at least a reference to the network as well. Dr. Sharma is involved, Dr. Hudler's involved in this too. So thanks, safe travels, and do you want questions now or wait? Thank you. Okay, sounds good. Yeah, thank you. Now I'd like to invite Dr. Andy Hudler, who is a fellow at the University of Colorado to talk to us today about emerging therapies and clinical applications for patients with non-T2 asthma. Thank you, Dr. Hudler. Yeah, so hey everyone. Good afternoon, thanks so much for sticking around. I unfortunately don't have any disclosures unless we can count all the lattes and cookies we've got to all enjoy over the past few days. So if we can go ahead and dive on in. So I'll be talking to you about kind of some new and novel therapies for patients with non-TH2 asthma, and then hopefully we'll be able to discuss the clinical applications of these therapies within this patient population and how this actually looks in clinical practice right now in our current state of being. So like we've mentioned many times in this talk, so TH1 versus TH2 high-low asthma kind of exists upon this continuum. They're not really distinct entities. But really we think of patients having these kind of distinct endotypes, where they either have a predominance of TH2 inflammation or TH2 low. And so our TH2 high asthma patients do have more eosinophilia, they're more steroid responsive, and then we have many biologics that we can use in this population. But we're more interested, like we talked about, in this TH2 low subset of patients and are interested in what treatments exist for them. So this is kind of adaptive. I'm sure we've all looked at this many, many times in clinic but our Gina Pocket Guide, as far as kind of our step-up therapy for our adult patients with asthma. So this is adaptive from that, just looking at our preferred controller medications and kind of this step-up therapy. And so we have kind of moved through all these steps up to step five and we start to think about what else can we do for our patients that aren't responsive to inhaled corticosteroid and LABA, despite how much we kind of step up that dose. And so a lot of these patients, like we've talked about with Dr. Sharma, potentially have some TH1-mediated disease and that may be why they're not responding as much as you would expect to high-dose ICS LABA therapy. And so really we have a couple of options within this guideline already. So we can do add-on therapy with teatropium or Spireva, which has been shown to decrease time to first exacerbation in patients, improve FEV1 in a subset of patients, and has been really beneficial for kind of this TH1-mediated disease, particularly if patients have fixed airway obstruction. Additionally, another option is to add azithromycin. So 500 milligrams of azithromycin, dose three times per week, and that was shown to decrease asthma exacerbation frequency, as well as improve quality of life and symptom burden for patients. So that's what exists currently. And so the question is kind of what else can we do beyond those two interventions? And this is where we really get into that inflammatory cascade again, looking at kind of this TH2 inflammation versus more TH1-mediated type inflammation. And we've kind of gone over this many times. We can see we have many biologics that target really that IL-5, IL-13, IGE, and then IL-4 type pathways that are all intimately interconnected in this TH2 cascade. We now have another biologic that targets higher up in this inflammatory cascade and targeting TSLP. And so what is TSLP? I think that's kind of important for us to know. So it's an alarmin, like we've previously discussed, that really affects not just these TH2 inflammatory cells, but really affects a myriad of cells within the inflammatory cascade. So looking at dendritic cells that go on to affect T cells, B cells, fibroblasts, macrophages, basophils, and kind of the list goes on. And so really targeting up higher in that pathway to help better improve inflammation that isn't mediated further down. And so what is TSLP? So it stands for thymic stromal lymphopoietin. This is an airway epithelium-derived protein. And then it's classically thought, like we talked about, to mediate the TH2 inflammation and asthma. But really there's an interplay in between all of these cell types. And prior studies have actually shown that higher levels of TSLP within the airways of patients with asthma have actually been correlated with worse airway obstruction, worse disease severity, and increased steroid resistance in these patients with higher levels of TSLP. And so what do we have to target that? And so this is our neurobiologic tezepilimab. And this is a human monoclonal antibody that actually binds specifically to TSLP and goes on to block its interaction with the TSLP receptor. And this is really important because this is our first biologic where we don't have these restrictions of, oh, your patient's eosinophil count needs to be this high or their IgE level needs to be this high. And there's actually no biomarker restrictions for use in patients with severe kind of treatment refractory asthma. And so why do we get to use this in this population? And so really this is coming out of a study looking at patients with severe asthma. They enrolled about over 1,000 patients in a phase three multicenter randomized double-blind and placebo-controlled study, so really well-designed. But they looked at patients that ranged from 12 to 80 years old with severe and uncontrolled asthma despite maximal inhaler therapy. And they looked at the annualized rate of asthma exacerbations. And so for the patients that were enrolled in the tezapilimab group, they were shown to have decreased exacerbations, improved FEV1, and improved quality of life. And more importantly, they actually looked at kind of by biomarker and these subset of patients, were they more or less affected by the use of tezapilimab? And so on the very left, we see the overall population of patients that received the medication. And so this had a statistically significant reduction in the annualized asthma exacerbation rate. And then if you look over to the next column, we see patients that had eosinophil counts less than 150 cells, and then eosinophil counts less than 300 cells per microliter. And there was a statistically significant reduction, ooh, tongue twister, for patients that had eosinophils less than 300 cells per microliter, and a trend toward significance in those with less than 150 cells. But that being said, they did have a much lower number of patients. So there were about 300 patients in each of the groups for the less than 300 cells, but only about 100 patients for those with less than 150. And as you can see, there was improvement in all of these patients, but a much more robust one when you look at the overall population. But very hopeful that we now at least have something to try to help our patients. And so you then again see this when we look at other markers of kind of this TH2 versus non-TH2 inflammation, where we look at patients, a fraction of exhaled nitric oxide, where patients that had less than 25 parts per million still had a benefit, even though it was not as robust as those that had greater than 25 parts per million of fraction of exhaled nitric oxide. And again, we see this with perennial allergenics, effective perennial allergens on these patients. So while the effect is not as robust as those that have a predominance of TH2 inflammation, it still is promising to kind of help patients with the overall symptom burden and quality of life and annualized asthma exacerbation rate. And so how does this look in clinical practice? And so again, we always pull out our little pocket guide of kind of what comes next. And so we've again progressed over to step five, and here we are at time to add on therapy with a biologic therapy. And so like we talked about before, this is our only biologic currently on the market that's approved for patients with severe asthma that doesn't have any biomarker limitations on it. So it really comes down to their control of their asthma, what they've tried in the past, and it doesn't come down to what is their peripheral eosinophil count, which can be helpful for our patients that are limited otherwise. And another option for our patients that's non-pharmacologic procedure-based is bronchial thermoplasty. And so this is a procedure that targets the smooth muscle within the airways, and is typically performed in three sessions over six weeks. So at zero weeks, three weeks, and six weeks, patients come in. And what ends up happening is they basically use this special tool that goes in and basically burns, essentially, and targets that airway smooth muscle. You can't actually always see the effect of it, and so what you need to have is a very, very experienced interventional pulmonologist that can go in, and you do airway mapping with this person. And during these three sessions, you basically start as distantly as you can, and then work more proximally in the airways. Typically, they target the right lower lobe first on the first session. Three weeks later, come back and do the left lower lobe, and then three weeks after that, come back and do the upper lobes combined. And they'll get anywhere between 40 and 70 doses through the treatment during each session. And like I said, it takes someone very highly skilled, and it does come with risks to patients. So they do have a much higher risk for poor asthma control and risk for exacerbation during this time that they are undergoing treatment. And so really, patients have to be optimally controlled, which as everyone treating severe asthma patients understands that that can be kind of hit or miss, depending on allergy season, or kind of virus season, or what's going on. So they need to be very tightly controlled as best as possible, and then have kind of a backup plan for if their asthma control does get worse. If things go well, though, you know, they can end up having a pretty good response. And so prior studies have looked at the effect of bronchial thermoplasty in patients with severe asthma and have shown that they have improved quality of life, improved symptom control, and fewer exacerbations. And this effect has been shown up to 10 years out. And so what are our future directions? And so like we've previously talked about, so there are a multitude of different therapeutic trials going on through the PRECISE network enrolling currently, and so please come up and get more information if you're interested after the talk. But really a lot of kind of therapeutics in the works, and hopefully we'll have a lot more to talk to you about in the next year or two. Our lab in particular has investigated kind of more of metabolism within the airways. And so we've looked at kind of the obese asthma phenotype and arginine metabolism. So we found that these patients have low arginine, which can then actually lead to nitric oxide synthase uncoupling and reduced fraction of exhaled nitric oxide in the airways. So we did a kind of proof of concept study that looked at giving patients 15 grams of citrulline per day for two weeks and found that in those patients that received that, they actually had increase of their fraction of exhaled nitric oxide, and they had improved scores on their asthma control test. So while we have a lot of work to do, something that is also promising is kind of targeting metabolism within the airways as well. So overall, the majority of treatments for asthma do target this Th2 inflammation, but we have shown that azithromycin, teatropium, and tezepilimab have all shown to benefit patients that have non-Th2 mediated disease as well. Always keeping in mind bronchial thermoplasty is a procedure that can be used, but does come with a pretty high amount of risk for our patients, and so really only used in severe, severe cases in the correct patient population. And that ongoing research is needed to continue to develop therapies for patients with non-Th2 inflammation and that is all in the works. So thank you all so much for coming. It's been great to meet everyone here, and safe travels. Thank you.

non-Th2 asthma

Th2 inflammation

novel mechanisms

therapeutic targets

metabolic dysregulation

obesity

asthma susceptibility

mast cell inhibitors

TSLP

bronchial thermoplasty