I go by Sexy Wexy, come on. To his left, traveling across the ocean from the city in motion, the emboldened great from the Golden State, hailing from the University of California, San Diego, Dr. Mean Green from Vienna, Africa. To his left, introducing, bringing no mercy from New Jersey, having his say from the Garden State Parkway, hailing from Rutgers Biomed and Health Sciences, Dr. Sugar Reynolds Panetteri. And last, but most certainly not least, our returning champion, our reigning pardon the disruption champion, the beast from the Northeast, pulling her weight in the Empire State, hailing from the Icon School of Medicine at Mount Sinai, ladies and gentlemen, Dr. Monica Artson-Kraft. Thank you. You'll note that Dr. Kraft, as the reigning champion, is the only one who did not, was not requested to submit an embarrassing photo of herself. So to review, the attendees should remember, but the rules of engagement for those of you who have not previously attended these sessions, is we will get to, we have about 13 topics, we will get to all we can, depends on how robust the debates are. For most topics, I will select speakers in a random order, I ask them to keep their comments brief, but I do get bored easily, I will move on and I have a buzzer to help us move on if need be. In the order of importance, volume, humor, and accuracy are encouraged, accuracy being you'll note the third of those three things, I reserve the cutoff speakers for going too long, being off topic, being generally unfunny and annoying, and note that I do come pre-medicated with Mountain Dew that's seeded with both extra caffeine and a little splash of motor oil to keep me well-oiled. Four points are available per topic, two for data and accuracy, two for a good attitude, you can lose points if you're particularly boring or getting attacked by an opponent, you're welcome to come at me, I warn you, I am also from New Jersey, so if you're going to come, you best not miss. Back to this year, audience participation, so if you've not already grabbed the paddle from the back of the room, I request that you do so, the savvy amongst you will realize the paddles have two sides, a thumbs-up side which is green, a thumbs-down side which is red, if you hear something you like or do not, please signal me and the audience can help assist or hurt competitors depending on whether you like what you hear, I ask that you use the data and not just the cut of their jib to determine whether you want to award points or take them away, for those who want to use social media, I hear that's a thing these days, the kids are using, you can go on, these days it's X, but Twitter and use the chest, PTD hashtag and then our later debrief which will be led by our guest color commentator, we'll be looking at those for comments after the game. Are there any questions, competitors? Alright, then with that said, actually I'm going to start, before I reveal the first topic, Dr. Wexler did submit the embarrassing photos of two of his competitors, so I'm going to go ahead and pre-award him a point for that, because that's how the game works, because as you know, for those of you who attended before, I am a benign, I'm a benign dictator, but I do make decisions based on somewhat arbitrary reasons, so alright, our first topic then, I will start with Dr. Wexler, remissing the mark, how do we define remission in asthma and is it truly achievable? Dr. Wexler. Such a great question, we want to get remission, remission is our mission, right? We want to try to get people to have normal lung function, we want to prevent exacerbations, we want to get people off of corticosteroids, but can we do it? Well, to date, we've only shown that we can do it in 30-35% of patients, we need better therapies, we have great therapies right now, but maybe we can do a little bit better. So I'd like to point out, you did not answer the question, which is how do we define remission in asthma, I'm going to move to somebody who may choose to answer the question. I defined it. No, no, you're done. Dr. Panettiere, can you try to respond to the question actually? Yes, well first I'm going to respond to my esteemed colleague Wexler, this is the newest snake oil, it is control, it's all about control, do you understand that? Control is important and control means no exacerbations, no OCS, can be on chronic therapy, but I'm really worried that we're selling something that we know exists for years and just returning it, so I'm not a fan of remission, I defined it, but I don't think it really is going to alter our therapeutic approaches. Oh, Ray, you're so naive, you know, think about it, we want to aim high, we don't want to just control symptoms, we want to go back to the early origins of asthma, and we really are, we're looking at the microbiome, we're looking at that atopic march, intervening early, let's go with prevention, and that's really where we're going, yes we have the remission to deal with, but I'd like to see us aim higher and do better, and prevent the disease. How do you cure something that, you're talking about remission before you get the disease, help me understand that, Dr. Monica. I'm happy to, you know, I love Ray, he's not always so bright, it's okay though. I'm here only to look good, I want to hear from Praveen on this. Yeah, no, David, I'm actually going to try to answer your question, so I think the definition of remission is you don't define remission, because it's right now made up. I think Monica and Mike like remission as a concept, because there's no data, and it's made up, but yeah, I think we can think about what is a marker of control and define control for asthma, but you know, using a remission definition, and I applaud people's efforts to try to put some structure around it, but I think right now, we're calling something a thing that's not a thing. But we can take people's lungs out, let's just take everyone's lungs out to evaluate whether or not they have remission or not, that'll help them, no? Well, their asthma's cured. Exactly. Good point. Exactly. I'm debating if I should give you a point for that, I will, because I liked it, even though it's sort of morbid gallows humor, but I like it, so we're going to go with it. Topic two, the Mod Squad. Should biologic therapies be used in patients with moderate asthma? Let's start with Dr. Ecclethildra on this one. Yeah, why not? I think we think a lot about expense and pragmatic things when we think about what therapies can be, where and who therapies can be deployed in. I think we need to be a little bit ambitious about what these therapies can do and expand the potential patients who can benefit. Then we obviously have to deal with cost at the same time, but I think, yeah, we should go there. Monica? I would agree. Actually, one of them's already approved for moderate to severe asthma, duplumab, so we're already doing it in a sense, but ICS over the long haul isn't great, and we know there's side effects, and we know even that patients who are on high-dose ICS exacerbate. I'd love to see the spectrum of what we can do with biologics broaden. I'd like to see more patients with moderate asthma really try them to see if they can even stop their other controllers. Wouldn't that be a great day? Last night, I beat Praveen in Papa's Shot basketball game, and I won this $100, so I want to contribute this to the next person with moderate asthma who can afford the biologic for his moderate asthma. Trying to decide if I should give you a point for beating Praveen at Papa's Shot. By the way, 17 out of 20 shots. It was incredible. I blacked out. I can't remember that that actually happened. Yeah, so this is the story of woulda, shoulda, coulda, but can't, because we as providers wish we could determine the trajectory of using drugs, but we don't because we have to play within the game of the MCOs. So also, how are you going to determine the metrics of success in moderate asthma when these are patients, by definition, are not on a lot of OCS, don't have a lot of exacerbations, and their FEV1 isn't that low? So I agree, maybe starting earlier is better, but how are you going to determine whether it works? And the cost is going to be blindingly expensive. Closing comment? Praveen, you want to go back? Yeah, Ray, you're assuming that a patient always progresses from moderate to severe. That patient might mean, what does early mean? I think there are some patients who you can make their quality of life better, who are labeled as moderate. You could reduce exacerbations that might have a lung function effect. So yeah, I think- Do you know that- Hold it, hold it, Praveen. I just want to comment that I didn't say that people progress. This is not cancer going mild, moderate, and severe. People who are severe asthma develop severe asthma early in childhood, and they just wheeze on into old age. That's Sir William Osler actually stated that. So I don't believe there's a progression. You're not going to prevent somebody going from moderate to severe, because they've gotten severe asthma way as a child, and they stay severe. Do you know that over 20% of the patients in the severe asthma trials who were on placebo achieved remission? I think we need to develop better placebos. Hey, they're good. There you go. Dr. Kraft, last word on the topic. And one other piece I'd say is, I think carefully selected patients, whether they're moderate, and I even have had folks I would consider mild at first, and then they had a very severe exacerbation. That's been published. We actually had a whole working group on mild asthma and how to deal with it, and there are a very small fraction, even those patients, who exacerbate severely. And so I'd like to say, I'd like to have, at least have those patients allowed to have access to the best therapies. I'm not saying it's across the board, but I think we need to be selective and really give our patients really precision-based care. Ray, I almost give you an extra point for pronouncing Osler correctly as a former Hopkins guy. Anytime anyone says Osler, it's Osler. I want to give you a point for pronouncing Ray correctly. I'm from Jersey, so as you know, we don't use the English so good always there. So I appreciate the feedback. Dr. Kraft, I'm going to go with you first on counterproposal. Given that primatine mist is over-the-counter, should combination ICS albuterol or ICS formoterol move to over-the-counter? Hey, thank you. I love this question. Back in the day, I had to testify when primatine mist was taken off the shelves because it wasn't in HFA, and then they wanted to put it back on. And we actually testified as part of the ATS and the Allergy Society that that's a bad idea, that patients were relying on a basically inhaled epinephrine, really dangerous. I am definitely for an ICS Saba over-the-counter that patients have access to. If it can be priced appropriately, patients have to be able to buy it and then work with their providers. But we all know our patients get into trouble on a Friday, on a Saturday. They run out of their meds. And this way, they'll have access. And as long as they partner with us, I think we can do that very thoughtfully. Rassy, you're nodding. Yeah, you know, Monica, this is one of the rare times I agree with you. You know, I'm going to switch this around. We say ICS Saba. That's wrong. It should be albuterol ICS. And why? Because the target is the airway smooth muscle. By the way, that's my favorite cell. It bronchodilates. And it bronchodilates better if you have an ICS on board. I think it's safe. It's usable. And I would love to see that PRN. I mean, I think that would be a game changer. Ray, this is one of the frequent times that I disagree with both you and Monica. I kid. But, you know, two wrongs don't make a right. I don't think that primatine mist being over the counter means that we should be giving inhaled steroid over the counter. So I would say no, again, to answer the question. Because, you know. Because he doesn't want to get more phone calls from his patients for prescriptions. Well, no, but he will get more. Yeah, he will. I have to take away because I don't follow your logic. I'm going to take a point away there. Again, I understand. I would push the taser on Wexler. That was tongue in cheek. Yes, I missed that. I'll give you the point back because I didn't catch the irony. But if you are going to be ironic, be more aggressively ironic in the future. And maybe it's a straw man argument, but I think that there are stakes to giving inhaled corticosteroids. It's not that because we're giving an over the counter bronchodilator does not. Maybe it's a bridge too far to be also saying we're giving over the counter inhaled corticosteroids. But I just want to make a comment that actually inhaled steroids are available over the counter in the nose. So what you're saying is, oh, you can't inhale it, but you can sniff it or snort it. And I don't agree. I mean, it's there. It's already there for God's sake. Patients aren't taking enough of their medications as is. We want to increase access for their medication so that they'll take them. The one way to increase access is to lower costs. The other is to make it available so they can just go and get it without having to call and wait three days to talk to you and to talk to you when you call them back. I completely agree. And I actually, I have a lot of faith in my patients. And I think they can decide if they're running out and they need to get a medication on a Saturday, let them do that. And that way they can be safe. We can take better care of them. And so as long as they communicate with me that they've done it, I'm good. I'm very good. I also call my patients before three days. All right. Ray, two things. One is you got a point for admitting you have a favorite cell because that might be the nerdiest thing I've heard up here in six years. And two, you do get a quote in the PTD, a file for saying you can't inhale it, but you can sniff it or snort it. I will be using that many times in the future. So welcome to the- Ray has a lot of experience with the sniffing and snorting. And that's only indicative- I want to say I have a Roman nose. It roams all over my face. So I know, I know. It's only indicated by when he speaks, actually. That's when we learn. I'm going to let Dr. Pita here go first on our next topic. You're so smart. Is PRN albuterol ICS the same as SMART? SMART stands for maintenance therapy. The albuterol ICS is rescue therapy. We're never, ever saying that you're going to remove maintenance therapy. For example, ICS LABA in lieu of SABA ICS. SABA ICS is a better bronchodilator and it's on-demand anti-inflammatory driven by the patient and using shared decision-making. Those are big, big words. It means they use it when they can and they should. Did you look at me saying they're big words because you knew I'm from Jersey and we've had that conversation already? Yes. You're probably North Jersey. What exit? You lose a point for referencing Joe Piscopo from the 1980s. All right, Dr. Craft, you're up. All right. So, Ray, you got to know your abbreviations. SMART is single maintenance and reliever therapy. MART is maintenance and reliever therapy. And then ICS SABA is AIR, anti-inflammatory reliever. It's a PRN. And so it's not really considered under this. It's sort of under the SMART umbrella in the sense, but it's really something, it's something different as you use PRN. Just want to make sure we've educated you on those guidelines. And I'm sure all my colleagues out there are very familiar with those eponyms and what they stand for. What I was talking about is a very user-friendly approach. I reluctantly agree with Monica on this point. Yeah. It's not the same thing. It's two inhalers, which is a, for patients, a different kind of experience. But, you know, whether they are as effective, that's another question, but it's not the same thing. Praveen, I don't know if you know this, but there was recently approved a single inhaler SABA ICS. There you go. You know, once in a while you can learn a new thing from us. So there are single inhalers you can use as needed. There's a lot of good data for as needed use of ICS SABA. So let's call that a maintenance therapy. No, it's not a maintenance therapy, but it's an as needed reliever therapy. I see the question. I want to mention something that frustrates me. We will never really have SMART here in the US, meaning single maintenance and reliever therapy. And that's because the FDA long ago did not really believe that ICS LABA used as needed was safe. And so now we're going to have ICS LABA as a controller, and then we'll have to use an ICS SABA as a reliever. We still have two inhalers, because the labels on our ICS LABA are not geared to SMART. And you can't get two inhalers a month for your patients. It frustrates the heck out of me. And so I just felt like I had to tell you that. Do you feel better now? I do. I feel very good. Oh, good. They have arms and they have those paddles for a reason. So you can't affect the scores here. They're all very even, but your input will make a difference. So if you hear something you like, give them a thumbs up. Did you see that thumbs up? Did you see that? Good job pandering to the crowd, Monica. That was great. Dr. Raff, that was a point away for pulling my attention to your thumbs up. I'm paying attention. I promise. I'm here. I'm here. Don't make me take a second point away. All right. We're going to move on from you're so smart to, but you're not my type. Is non-type 2 asthma a real clinical entity? Let's start on the far side of the table with Dr. Wexler. Is non-type 2 asthma a real clinical entity? Absolutely. Patients have eosinophilia, yes. Patients have high nitric oxide, yes. Patients have allergic asthma. But there's so many patients who have asthma who don't have any of those biomarkers. Now, there can be a range and dynamic component of asthma. Sometimes you're exposed to an allergen. Sometimes you're exposed to a virus. Those can modulate different pathways. So definitely, there's non-type 2 asthma. We all see them. They're hard to manage. They're hard to control. We have to develop better therapies for non-type 2 asthma. Let's bring it down the line, Dr. Wexler. So I think non-type 2 asthma is kind of a lazy term, because how do you define a negative? Who went to my excellent talk on non-type 2 asthma? Yes. All right. Yeah. You know, so. Those were the five people there, right? That was at least 15 paddles. Actually, they're family and friends out there. I actually paid for about, yeah, 20 registrations for this. So no, non-type 2 asthma is not a real clinical entity. It is a group of things that are defined as a negative. That doesn't mean that patients who don't have type 2 mechanisms aren't an unmet patient need. But I don't think that I don't like the term non-type 2 asthma as a specific clinical entity. I'm going to refine that and say there isn't white and black. There is not high T2 low. I mean, I favor the concept of low T2 rather than no T2. And what that suggests is there is smoldering inflammation. It may be is an affiliate. It may be 13 and 4 driven. It may be IL-5. Even in the low T2 patients. So I think we should consider this as high T2, low T2, a continuum rather than white, black, and make it so dichotomous. All right. So Ray, do you know that in certain kinds of asthma, you can get type 1 inflammation and type 2? So I'm with you there. But I see folks where I have looked up and down for type 2 inflammation because I'd really like to find it. And I don't find it. So I think there is a fraction out there who don't have type 2. Now, I agree with Praveen. I hate the non-type 2 name. I feel like it's sort of the path of least resistance. And it sort of demonstrates that we really don't know what it is. And so I'd like to come up with really understanding the path of biology better so that we can actually really phenotype these patients in the clinical arena and offer them therapies. And so one is potentially looking at IL-6. That's an interesting one. So there's some patients who have type 2. That's an interesting one. So there's some patients who are obese, have high blood IL-6 levels, metabolic syndrome, and asthma. Wouldn't it be interesting to know a little bit about them and be able to give them a therapy? There's some anti-IL-6 therapies out there. Yay, thanks, guys. Glad you agree. So at least we have an option. But we've got a ways to go in this space. I appreciate you guys reinforcing the excellent talk that I gave on non-type 2 asthma an hour ago. No problem. Let's move on to self-control. We'll start with Dr. Akifoto. Really? That seems ironic. I'll give you a point for that. Point granted. If a patient with severe asthma who's well-controlled on a biologic stops their background ICS lava, how would you counsel them? That is a tough one, right? Because we have patients whose third-party payers might not continue their biologic. So there's pragmatic reasons to tell them to. I've actually told patients to fill your prescription. Maybe you feel good enough to not take the medication, but at least fill your prescription. And I think it is an outstanding issue to understand whether every patient can potentially withdraw their background ICS lava. What's the underlying risk proposition of not being on ICS lava for these patients? That's a completely data-free zone. And I think in the realm of having PRN-ICS albuterol, where we have some titratable ICS available to us, I think marrying this concept of withdrawing background maintenance ICS lava and maybe incorporating PRN instead, this is going to be a good area for investigation. Totally agree. Love that. I think patients will stop their background without letting you know anyway. So I try to do it with them in such a way that they can do it safely. Because I think at the end of the day, I do love the concept. But I am struck by the problem when it comes time for renewal. And the insurance companies look at the refills, and they said, you know, this person needs to be on three more months of consistent ICS lava or they don't get their biologic. And that, it's counterintuitive, because the biologics target inflammation. And if they're doing such a good job, the patients don't need all the other medication. So I think we need to do better around the indications for biologics and what carriers ought to cover in that setting. You know, it's really interesting, because both Praveen and Monica, I'm on board with that. But I don't know if you're aware of it, but patients don't take the medicine like we prescribe. And I know that that's a revelation. But I think the important point here is what we're playing to is not the patient, not the patient's care, but to the MCO. And that's the wrong people that we should be playing for. So yes, Praveen, your patients are bankrolling their controller, just put it in the closet, don't use it, just get it refilled. So they have futures in ICS lava, not using it. And that's a problem. I think what we need to do is inform the MCOs and have an effect where we realize, actually, they win, because there's less cost if the patient doesn't need, doesn't need the maintenance therapy. I mean, that's a win. We definitely need to. Thumbs up. Stop. All right. I'm going to formally request the contestants to stop directing me to the audience to look. I'm good at this. This is all I'm good at. Let me do my thing. All I'm good at. You guys are great. Keep doing it. We definitely need to speak up against the payers and tell them what we think is right for our patients. That's first of all. Second of all, while my colleagues are sharing their opinions about this, there are actually data presented at the ERS where the results from the Shamal study, presented by David Jackson, which showed that patients who were on a biologic, in this case, Benrelizumab, were able to safely titrate their inhaled corticosteroids and LABA off without a significant increase in exacerbations and without a significant decrement in lung function. But you still need to check biomarkers, because a subset of patients continue to have some elevated nitric oxide and had a decline in their lung function. So yes, we can do it. We just need to figure out exactly who, and we need to monitor our patients. Yeah, I was just testing you to see whether you actually read journals, but good job. So no, I think the interesting thing, too, is we give biologics in very different patients from who is included in trials. I think we all know that. Even when I'm trying to recruit for trials, when everybody on this table is trying to recruit for trials, it's a very different type of patient. So we're already kind of in that zone. So why is having somebody continue their ICS LABA any different? And I'd also say, if you look at the literature, Martin Parker. Look at the literature. Just look at it. Yeah, just look at it. You don't have to read it. You don't have to just look at it. The important point is that we need to embrace what patients want, and in that particular paper, Partridge clearly demonstrated what the patient wants is not maintenance therapy, not continuous therapy. They want it sporadic. They want to do it on demand, and we're ignoring that. Either it's the MCO or the provider. I think we need to come back and ask the patient what they want, and what does success look like to them? And many will say success is not taking my medicine every day. Oh, I just want to say, comment on, to Praveen about my reading articles. Some of you might know that I'm the associate editor for Chess, and I've got a great editorial staff. My assistant editor is, or so-called assistant editor is Praveen, but he's really just the assistant to the associate editor. If we're gonna start dropping chess titles, I got you all beat, okay? So let's leave that on, let's leave that away. Leave it away. I'm the Dwight Schrute of the asthma section. I'm happy that you look at the literature. I'm proud of you. Very good, very good. Next topic, Tez is more. Is tezapalumab actually a type two biologic? Let's start with Dr. Kraft. All right. I was actually gonna ask whether it's a non-type two biologic, that's the other question I have, but I think the data in type two asthma, other than in oral corticosteroid dependent, looked reasonable. You know, I think we're still getting a lot of experience with it. I worry more about the non-type two side because they've defined it in the studies as less than 300 eosinophils, which we know that from 150 to 300, in some of our eyes, is still type two. So I think the jury's still out on the non-type two side, to be honest, but type two, I think there is some benefit. I'll be honest with all of you, I'm still gaining some experience with it myself, and oftentimes I'm using it, I'm prescribing it for patients that have failed other biologics, and so therefore, I don't, I don't know, I'd love to hear from the panel. I don't feel like I'm quite as convinced that it's my go-to, necessarily, for type two asthma, but I think it's nice to have a choice, especially, and you know what's gonna, what I worry about more is we're trying to be really scientific about what we choose and phenotype our patients and really be thoughtful. I'm worried that the insurance carriers are gonna dictate what we get to try because there are six choices now, and that is what worries me more, and so are we gonna be able to give our patients the best treatment? So, you know, I think the data is quite compelling that Tessie is really a person for all seasons, and what I mean by that, it's both high and low T2, and actually, the biggest signal was in the high T2, so you know, yes, you don't need biomarkers, but you use biomarkers to show engagement of the target because phenotype goes down, the years go down, and actually, total IgE goes down at four months, so I don't need it to start it, but I do know if it works using a pharmacodynamic biomarker of engagement of the target. I'm pretty, I think it's a great drug. I think it can be used in high T2. I typically would use that as a change drug if you fail, and in the low T2, there is nothing else. This is that space, so you know, it's a person for all seasons. Good job, Ray, in contradicting your prior point about there being kind of a gradation of T2-ness in patients, and I think tezapelumab is probably the poster child for that, right, that even somebody who's got low biomarkers, the fact that you could argue, and I do argue, that a lot of what you're seeing with biomarker-low patients is underlying, that the biomarkers are inadequate, and they don't necessarily reflect some airways, so you're reversing your opinion that you talked about no T2, right, because now you agreed with me that there is T2, but I just didn't want to say it. It depends what your definition of is is. Boys, boys, stop fighting, boys. I've never been happier to say that watching this interaction is so tiresome, but it's wonderful. Tezi is a T2 biologic and a non-T2 biologic. It works across the spectrum. It works well in the type 2 patients, and it lowers exacerbations in non-eosinophilic patients, patients with eosinophils less than 150. It works well in patients who are non-allergic. It works well in patients who have low pheno. It works well in patients who have combinations of those biomarkers, so yes, it's a type 2 biologic, and it's a non-type 2 biologic. It works upstream to address all of these issues in a broad spectrum of patients. Hey, Mike, I had a patient start it and never played tennis and played tennis after starting that drug. That's good. That's great. Sounds like it's an amazing drug. Thank you for that important point, Ray. The joke is he never played piano and he started playing piano. That's the right joke, Ray. Exactly, exactly. Drop the mic. Exactly. That's some great evidence-based medicine. Thank you. I'm with you, I'm with you. I've had some successes. I just feel like I haven't had as much experience with it as with the others, so that's why I'm a little more conservative than you guys. I don't just willy-nilly just give anything. Shocked to hear that. All right, we'll go to Dr. Penetiri first. On Make Mine a Combo, is it ever appropriate to use combination biologic therapy, and if so, in what way? Yeah, so combination biologics, and I use this imagery to my fellows. I said, you know, you got a Corolla, but if you're gonna use two biologics, you're in the Lexis category. You really, that's a lot of money. The other interesting aspect is, I have a lot of patients on dual biologics for other indications, like rheumatoid arthritis. They're on anti-TNF drug, and then they'll get an anti-high T2 drug. What it told me is there are some biologics like the anti-TNF that don't affect asthma at all, because otherwise they wouldn't look for a second, and I think on occasion, there is a role for combos. Now, whether that combo can be used specifically for asthma or not, it's gonna be a tough hill to climb to get MCOs to agree. I think there's one scenario where you can do it, and I know, Praveen, this is like PTSD. We debated this at ATS, but there is one scenario. If your patient has chronic rhinosinusitis and nasal polyps, and is symptomatic, you have a couple of choices for that, and you can start that, and it'll improve their asthma. If it doesn't completely improve their asthma, you can actually add a second biologic for the asthma that's not necessarily approved for CRS with nasal polyps. I've done that in some scenarios, and it's really lovely. It is expensive, though, so I just do this in very carefully selected patients who are really having a tough time. I wanna go to Ray in a minute, but I wanna hear from the audience. So what does the audience think? Is it ever appropriate to use combination biologic therapy? Thumbs up, thumbs down on this. So it's a slight, it's almost 50-50 split. Dr. Wexler. Yeah, there are patients who have multiple mechanisms of disease that are prominent. There are patients who've got multiple comorbidities. The issue is the cost. So yes, here's that $100 bill again. I'll give it to the patients who can afford it, who can't afford it, but we want it, and Praveen keeps on taking it away. He gave it to me last night. He's taking it back now. Praveen, the ink runs when you touch that bill. If the patient needs it, you gotta try to fight for it. You gotta try to fight for it for multiple mechanisms. What we really need are better drugs that will address all the different pathways and better biomarkers to help us identify who can respond to which therapy. So is the issue the cost in your mind? Is that the only real issue? There are no safety issues that we know of to date. There are not a lot of data to evaluate that issue. So for now, the issue is cost, and also demonstrating superiority over monotherapy monoclonal antibodies. Yeah, I think Ray's managed to offend every Corolla owner in this room, but I'm gonna contradict my assigned position from when Monica and I debated this a few months ago, but I do think there are patients in who it's appropriate because type two inflammation is not a monolith. There are some, but I think we need to probably be better and further work to understand what portion of exacerbations are eosinophil mediated and in what patients and what proportion of exacerbations or decline in lung function may be driven by other type two mechanisms. My gut tells me that there is a role for depleting eosinophils with biologic therapy and reducing IL-4 receptor alpha signaling in certain patients. Hide this topic up nicely. All right, we'll start on this end this time. Dr. Kraft, roll the taper. Other control, controller, forgive me. I'm gonna take a point away from myself for that misspell. Can other controller medications be tapered when a patient is doing well on a biologic for severe asthma? So a lot of the panel has talked a little bit about trying to minimize medication to make it easy for patients. What are your thoughts on this? Definitely, absolutely. If they're doing well on a biologic and they don't need the background, we've already talked about the fact that patients are gonna probably do it themselves anyway. So let's do it in a really thoughtful way. And I love the idea actually of this ICS-SABA option if they are so fortunate as to be able to come off their ICS-LABA. And again, they may do it themselves, but I'd rather do it with them in more of a partnership shared decision making situation to get as low as possible. And if they're able to come off, they have the ICS-SABA to lean on, which will be coming actually I think in early, in I think second quarter 24 is what I hear. Does anybody think, I'm curious, does anybody in the panel think no to this question, that we need to maintain the other controllers in the context of a well-controlled patient on biologic therapy? No, not at all. I mean, I love killing drugs. And you know, the one that I kill immediately upon seeing the patient is montelliacast. So I get a lot of referrals in severe asthma and they're on montelliacast and I go, well, that's one we're gonna kill. We don't see a lot of value as pulmonologists in the use of that drug in severe asthma specifically. So I think there's a whole lot of medicine that people add and never take off. Matter of fact, in the chronicle study, which is study of biologics, do you realize that 65% of patients who got started on the first biologic are continued on the first biologic? Does that mean we're smart, that we got it right? Or is there a threshold of energy that's so high that we won't wanna change somebody because it's just too much effort? That's an issue. That's how I live my life actually. But I think it's important to point out that high-dose ICS is not a free lunch. So we have to remember that, particularly on a population basis because we give a lot of patients a lot of high-dose ICS. And for an individual, maybe that's fine. But from a population basis, we do have to think about reducing high-dose ICS. Yeah, I think we need to consider this in all of our patients, reducing costs, reducing morbidity associated with inhaled steroids. But we need to do this in a thoughtful way. We can't do it willy-nilly. We have to evaluate, continue to evaluate biomarkers to figure out which ones are safe to taper and when. Another thought might be to taper the biologic or increase the interval in an off-label manner to evaluate, maybe we can cut back costs that way and see if instead, maybe we can increase the interval, go out every other month with the biologic. We've shown that we can do it in a subset of patients. Who are those patients who might benefit from that strategy? Right, I like that idea. I've done it, and I think that's a great thought. I do run into trouble with renewals when I start doing that. I don't know if you've had that issue, but it is absolutely worth a try. And I also wanna say that the ICS-SAVA for specialists is actually available now. And you can get it as early as January widespread. So I wanna make sure you know, because I think that's gonna be a nice addition to our armamentarium. I wanna go off-label and talk a little bit about this increasing the interval of biologic dosing. Again, show of hands in the audience, a thumbs up, thumbs down. How many of you have prescribed off-label a decreased interval frequency for biologic therapies? Increased interval. Oh, increased, oh, I'm sorry, yeah. So decreased frequency, increased interval, thank you. Pointing off myself. So a surprising number, about half. Pam, have you all done this? No, you know, I get a fair amount of patients who know precisely that they're in their third week before they get their next biologic, and there's turbulence. They feel like I'm not feeling so well, especially in drugs that are every eight weeks. I find someone will come to me and say, you know, that seventh week is really hard, and I'm using my rescue. But for patients, well, so I think Mike was referring to patients who are doing well on therapy. Would you increase the interval, decrease the frequency of biologic therapy off-label? Well, I guess it's a value proposition. What's the downside? The downside is it's gonna make me get it harder to get it approved. So, you know, I use, I'm a molecular pharmacologist. I like to use it. He's a molecular pharmacologist, so maybe, why don't you talk to the patients, actually, and see how they're doing and what they want. I think most of them want to take drugs less frequently. I think you made the point, you've done this. I've never seen Ray silence a little. His mic is working, ladies and gentlemen, I promise. No, no, no. Yeah, yeah, yeah. He's still with us. CPR, we need CPR here. Actually, some of my audience might want PCR. Unlike National Jewish, we actually examine the patients rather than order tests. I mean, you order a high-res CT scan, every other test known to mankind, then you go in and say, hello, I'm Dr. Wexler. I'm Dr. Wexler. Praveen, you raise your hand, you've done this. How could I follow that? That's not fair. You gotta try, man, you gotta try. Yeah, no, I have done this. I think that for certain patients, it's about patient-centered care, it's about shared decision-making. A lot of patients desire this, to be on less medication, even if the medication's working well. I do, in some selected patients, increase the interval. Yeah, I would add to that. If the patient's not doing well right before their biologic, we're not gonna increase the interval. Why would we do that, right? We wouldn't do that. We talk to our patients. We know what they are experiencing, and we wouldn't do that. But then some others who are controlled, you can, and it actually does work. So I guess the question, Monica, is let's go down that road and rabbit hole. So now I extend the time, and then the next three months, they notice that they're actually getting short of breath again. And now you've extended it, so what do you do? You go back and shorten that interval, and you don't have problems with access for managed care. Not yet. And that N is one. You need to have a personalized approach, and you're not gonna do this in every patient, but in the subset of patients who are doing well and who, through shared decision-making, want this type of approach, and who may not be able to afford their monthly copayments, this might be a good option that could allow them to access their medications when they need it for their specific type of disease. I agree. We have time for about two more topics, so I'm gonna take a host's prerogative and jump to phenodilurents. What is the current role of pheno in the diagnosis of severe asthma? Let's start with Praveen. If you went to my other excellent talk two days ago, you'd, uh. Yellow card, yellow card. You're not allowed to self-reference. So Praveen, all we hear is excellent, outstanding talks by your own criticism, so do you have any that are not so good talks? No, I don't. Okay, let's address the question. Ray, this one. I'm glad. This session. This session, right. I'm glad we straightened that out. So I would say that the yellow card was worth it, and the pheno does have a role in the diagnosis of severe asthma. I think it's still being defined. There are some, you know, I think pheno in other clinical contexts, taking other context clues, can have a role in diagnosis. Recent ATS statement talks about this a little bit. Again, as a frontline person, it's hard to actually say X pheno equals asthma. That's not what we're talking about here, but an elevated pheno in the context of symptoms can point toward an asthma diagnosis. You know, it'd be great if my co-panelists read the guidelines. Really good, especially if you're gonna sit up here. Actually, there's not a real place for pheno necessarily in the diagnosis. In pediatrics, there's talk about using it when the lung function is normal, and there's not a lot of reversibility, so you don't have that piece, and in adults, in allergic rhinitis, you can have an elevated pheno. There's other scenarios. In eosinophilic bronchitis, your pheno can be up. So you have to be careful that, as a standalone, it's not gonna be enough. So I wanna make sure I understand before you jump in. So you believe there is no role for pheno currently? I think it's adjunctive, but it can't be used as a solo to diagnose asthma. Right. Yeah, that's scary. I actually agree with Monica. You know, it doesn't have a role in diagnosis. It's best played in the longitudinal follow-up of patients where they serve as their own baseline, and it goes up and down. I think that's where pheno really plays a role, and I agree with Praveen. It's all about context. The context that the pheno is high or low really makes a difference. So the isolated test in its own, forget about it, that's New Jersey. We really- I'm gonna take a point away from that. Sorry. No. I mean, I'm not surprised that Praveen doesn't remember the literature from before 2000 because he was in elementary school and didn't remember it. And I'm not really surprised that either Ray or Monica forgets the literature because they're a little bit more senior, and they may not be remembering all literature. But we published good data when I was a young pup as a fellow, showing that you can use acetylnitric oxide to make a diagnosis of asthma. In fact, the receiver operator curve area under the curve for acetylnitric oxide was higher for acetylnitric oxide than for blood eosinophils, for IgE, for sputum eosinophils. All you had to do is have a clinical history and add that to acetylnitric oxide. It goes down when you give patients inhaled corticosteroids. It's clearly a marker of IL-13 activity. So I'm not sure what my colleagues don't remember the literature. Sweetheart, why did it make it into the guidelines then, if that's such a fantastic study? I'd also say that, has that study been repeated? I think what you just said confirmed what we said, right? He said, pheno's really important, especially within the context of history and physical. Not stand alone. No, absolutely, by the way, it can be used on its own in the diagnosis of asthma, on its own. Pheno discriminated a subset of patients in a study of over 200 patients that showed, compared to controls, levels of pheno were discriminatory. There's a whole receiver operator curve analysis that you can look at. I think we're gonna have to arm wrestle over this one. I think, I think there's no other option. I also didn't realize that pheno in the 1950s when you were a fellow. All right, last topic, last topic. I was submitting a lot of gas back then. Wexler, I'm gonna let you start on the last topic. Are current biomarkers good enough for asthma management or do we need to look for something new? They're okay for asthma. They help us identify what type of asthma patients have, if they're eosinophilic or not, and they're pretty good. If the levels are really high, it often points to the pathway that's dominant and that can help guide your therapy. But we need better predictive biomarkers of who's gonna respond to what therapy. Using eosinophils down to 150 is usually not that helpful. We need also better response biomarkers, pharmacodynamic biomarkers that'll tell us whether or not a therapy is working, working well. And we don't always have that. There are many other pathways that are going on that we're just not able to comprehend or put into context. We've studied LIGHT, L-I-G-H-T. It stands for some long acronym as a biomarker. And that suggests that there are so many other pathways, IL-6, CRP, urinary bromotyrosine. We're not using any of these. We need to validate them and we need to identify novel biomarkers that'll help us manage our patients. Completely agree, and actually, there's some really exciting things going on. Mike mentioned urinary bromotyrosine. There's also eosinophilic peroxidase by the Mayo Clinic Scottsdale Group. But there's also some companies out there that have this next-gen sequencing, and there's one I'm working with that can do immunophenotyping on the one hand and microbiome on the other to look for, actually, evidence of replicating organisms as well. So you've really put together the microbiome and the immunologic phenotype as a point of care. And they're looking at doing this just in non-induced sputum to start, hopefully nasal swab. That is really the wave of the future. Yeah, you know, I tend to agree with my colleagues, except the current biomarkers are a coarse rheostat. They're coarsely giving us an idea that this is important or that is important. What we need is a fine rheostat that really allows us the precision of knowing which cell is being involved so we can target the cell. We have zero biomarkers in the low T2 space, defined as the lack of high T2 biomarkers. What an awful case definition. There, we need something. Sure, IL-6, maybe that's gonna work, although the current studies aren't really positive in that space, and as we're using anti-IL-6. So we are far from the perfect signature that allows us to determine a predictive therapeutic response. So the answer is that current biomarkers are not good enough. That doesn't mean they don't have some really useful value. And we need to be better about using our current biomarkers, but at the same time recognize that they have limitations, that there are many patients who are biomarker high who may not respond to the way you expect to therapies. There are patients who are biomarker low who we are denying therapy to who might respond to T2 biologics and other therapies. So we do need to use omics approaches, multimodal approaches to have a better set of predictive biomarkers that are more modern in their. So Praveen, I have to ask you a question, given what you just said, that our biomarkers are okay and they're not bad. Do you still have VCR tapes? Yeah, sure. He's got an 8-track stereo, though. 8-track, yeah, I play music and they play. He was in high school then. He doesn't know what we're talking about. I'm more of a Betamax guy, Ray. I have to give the final, you pulled off a tie with the VCR tape comment. Can I just add? Although the self-referential Betamax self-slap by Praveen also gave him a point, so that was pretty good. Can I just ask Monica and Praveen to explain what Ray's stance is on type 2 or non-type 2, because he keeps on flipping and flopping and flipping and flopping. I have no idea. I simply use it as an incorrect shorthand that my colleagues have embraced. I'm gonna pull back. So we have a bit of a barn burner. We have one final challenge for our competitors, but before we do that, can I get a round of applause for these four folks, please? Thank you.

panel of doctors

asthma management

biologic therapies

remission in asthma

combination biologic therapy

phenotyping in asthma diagnosis

biomarkers in asthma management

research in asthma management

patient-centered care