Andy, a clinician might say, and tell me if they'd just be out and out wrong, that before going to a fairly expensive therapy, as all four of them would be, that the patient should actually be on oral corticosteroids, and then that therapy added when a low and well-tolerated dose of them cannot be achieved, and then you use it to kind of try to reduce exacerbations or back off, or both. In other words, is this a little bit, and many of the people enrolled in trials had that as an endpoint, so is this kind of an early jump to immune modulators other than corticosteroids? You know, I don't think so. I think general guidelines kind of have clinicians shy away from using corticosteroids as a controller. This particular patient has symptoms, but he's not necessarily having an exacerbation. He's kind of having chronic symptoms. So I think I would say that I would favor risks over benefits of going to putting this person on steroids before, but that's, you know, I'm giving you my opinion, and a little bit of guideline with avoiding steroids, as we all know, so I'm not sure if that answers the question. But I think, you know, for many of us, we do hit the biologic trigger much sooner now than ever before, so I don't really know how to answer the question other than, like, kind of practice-related as opposed to guideline-related. I mean, there's also a literature about how poorly, or well, how well, but maybe not as well as we'd like, put it that way, IgE and eosinophil levels predict responsiveness to just those anti-cytokine medications that ought to do something about that. But kind of at the root of the question is that because it doesn't seem like a type 2 reaction this patient, or endotype this patient has, that leads you immediately to zeppelin myelin. So is that a correct biologic leap to the bedside that we can make? I think it's a reasonable clinical consideration. If the patient's insurance is not going to be covering it, that's sort of why maybe to answer your question is why I put that last line in the commentary, where it's the selection of the therapies depends on inflammatory response, depends, et cetera, patient preference and their prescription plan coverage, sort of to bring in all the different elements of what may permit or deter the use of these agents. I was actually going to generate a question myself in this area, and maybe I still will. I'm kind of sitting on the fence, but I'm kind of looking at the New England Journal review from January. I don't know if it's in your references, but they start the section choosing initial biologic therapy, and they say, since no data from head-to-head RCTs comparing the efficacy, real-life effectiveness, and long-term safety of monoclonal antibodies in patients with severe asthma are available, high-level evidence is lacking to guide clinical decision-making. It's like sentence one. Yeah. Yeah. No, I totally agree with that, and that's why you take care of, if you watch a group of asthmatics, they're on a bundle of different biologics, but I could make, if the sort of hesitation with the question has to do with his not being on, or maybe I can make him steroid-dependent, and then it would be clearer that a biologic, because if your choices are putting someone on a biologic versus maintaining someone on steroids, that I think most people would agree that they should get a trial of being put on biologics. I think I would, I mean, I'd love to hear from other folks too, but I think I would like that, and then I might even, because I'm not sure where the question resides between, it isn't a guideline, like a well-accepted guideline, well-established with a high level of evidence, and then, of course, there's how you would do it, but that shouldn't be a basis, so it seems to me it's somewhere in between those two extremes, and you could give, you could, in a sentence or two, you know, indicate that he's up and down on steroids and rarely can get off them or something, and that really strengthens for the average practitioner moving to something more, and secondly, would you even be willing to say, based on the, you know, the inflammatory endotype here, which would be the most reasonable antibody, because then the question is testing in part that they understand choice D seems to be less important to the type 2 inflammatory response, whether that bears out as they all get compared head-to-head, if that ever happens, you know, yada, yada, yada, I don't know what trials are in the offing between the MABs, but that might just even strengthen that answer a little bit more and require that they understand the mechanism of action of these four drugs, which they probably should, you know, like I think, okay, I don't. Yeah, no, I think that's, I think that's a way to sort of take it out of the guideline or expert opinion piece, still ask the question, still teach about the non-T2 pathway. I would have to take out dopilimab as a choice, but there's plenty of others that can be placed instead. So, because dopilimab is indicated for chronic steroid dependence, regardless of endotype, but I think that that is a way of moving it forward without getting to put up on on guidelines. Andy, if you did that in practice, if somebody is steroid dependent, which of those two agents would you reach to first? I would personally go with dopilimab. It's been around for a longer period of time, you know, I'm more comfortable with its use. So I would, you know, and I could just take it out and then add it in my commentary that it would be a reasonable alternative and talk about its pathway. I'd be just a little nervous if that is the go-to in the situation of your question or of your case, that it's not there as a go-to, you know, if you make this patient steroid dependent and practice would be to use dopilimab, but we don't even include dopilimab. I'm not sure it's... I guess I could find a contraindication to dopilimab. I like it a lot too, that I don't know the field sort of well enough. Is just saying severe asthma, is that a clear enough description of the indication for this drug? Is it in looking at the, you know, the two studies here, it looks like people with eosinphilic asthma did have a better response to this even than those without, right? So is it, can we define severe at all here or is just severe is good enough, you know? Yeah, no, and in a sort of like a looking at this the other night, I added a severe dependence defined as two or more asthma exacerbations in the previous 12 months requiring use of oral corticosteroids or dependent on oral corticosteroids of at least five milligrams a day of prednisone or the equivalent. Could you just replace choice D with omalizumab and then A becomes the right choice, but you're free to discuss both dopilimab and tezapilimab in your commentary as you have. I'm hesitant. Well, you know, I think this whole sort of epithelial cell driven pathway of asthma inflammation is a new hot area and it is completely different from the other pathways. But if an anti-IgE drug, you know, is as good as anything, even when the IgE levels are normal on several determinations, then it throws it up for like, well, you know, maybe there isn't the easy rationale for picking one over another. I'm worried about that. Yeah. Yeah. I mean, I think the selection of it in general is dependent on, you know, right now for insurance purposes, you have to prove the eosinophilic inflammation, whether that turns out to be, you know, an accurate predictor or not is, you know, it's different from practice. Current practice is using some marker of eosinophilic inflammation. Some even favor the pheno. But again, some marker of eosinophilic inflammation. But, you know, I could, I will modify as the group feels. Could you accomplish both by changing to omalizumab, as Jesse's suggesting, putting the patient on steroids, making the right answer, dupilumab, but still talking about this new pathway. And Tessie is in your commentary. And so still making, putting the teaching there, but not having, staying away from the controversy of. Of the dupilumab? Yeah. Yeah. I think I could, it doesn't get away from Jesse's point, but it makes, you know, omalizumab, you know, a clearly incorrect answer. But I think if I understand Jesse here, it's not so much of like, what's the correct answer. It's how it matches clinical practice. Well, no, I mean, I mean, I guess there's a bit of both here. It's like, is there, there's this new class of drugs and that's great. And they, and they should learn about them. They have a shortcoming of being the new class of drugs and, you know, maybe expensive, difficult to get clearance for them. And we don't know their long-term effects as well as we know some of the others. So if you're going to ask people, what's the right drug to pick, the best drug to pick, and you know, and it's a, it's an error to have two in this class on the list, because some people are using one and some people are using the other, then you want to get down to one of them. We've already had that comment from Peter. That's great. And I think valid. Then it's like, can you find against either one of those two, if having both of them in the choice is difficult and a little unfair for the test taker, can you find three really wrong therapies, you know, three. Now you've decided to only have MABs up there. You could have, you know, two MABs and make no change at all, or escalate the steroids. That might make your life easier. And you can address that in an upfront sentence and say, well, you know, more steroids, probably not a good answer. This is severe asthma for the reason of the definition of it. And going to another biologic is, or going to a biologic at this point is a good idea. And I, you know, and then I'm off and doing nothing isn't a good idea either. So, you know, you could pick type two inflammation focused, or you could pick something else and you should probably pick something else in this case, because all the evidence is it isn't type two. That's another approach. But if you think you can get three MABs that are really wrong, that nobody ought to pick them for whatever set of reasons you're going to come up with, then you could fix the question by just, you know, eliminating choice D here and sticking with A. That's how I see it as a test taker. Does that, does that make sense to you? So I agree with getting, changing dupilumab to, I like the idea of putting them all MABs because it gives a little education about the MABs, though increasing steroids is also plenty to talk about. So I guess what you're favoring is shying away from TESI and moving it. Because I kind of agree with Peter's comment, which is, okay, if you got two MABs there that are options when it's not type two inflammation and you have severe asthma, not controlled well enough by what you're doing, hence the definition of severe asthma, poorly controlled severe asthma, then you, you know, you got to pick just one of them if people are kind of split down the middle of what they're using in real practice. You know, unless a guideline tells you one's really better than the other, that clearly hasn't happened. So that's the problem with the question to make it. I guess he's not oral, I guess, you know, the way the patient is written, he's not oral corticosteroid dependent and dupilumab is indicated for oral corticosteroid dependent patients. So dupilumab would be an incorrect, when you asked your question, I thought you said, is he, if this was an oral corticosteroid dependent patient, this patient is not oral corticosteroid dependent. He's only gotten, he hasn't had frequent exacerbations and he's only had one dose in the year. Yeah, but if you made him such, then the only, and further strengthening the, his severe asthma status, is it true that you always start with omelizumab? You're getting me crazy here. Is it omelizumab or dupilumab? Omelizumab, yes. No, we don't really use omelizumab. Would you always start with that first, then it's a wrong choice. Yeah. I think people start, not too many people really use omelizumab all that much anymore. The Zolaire, you know, it's more along the lines of, of MEPA, you know, or some IL-5 or dupilumab. Those are the ones that are, that are most used. I have another question that I wrote about dupilumab that may be part of my inner resistance. So if I change this to a dupilumab question, then I'm going to have two dupilumab questions. So I, you know, I guess I would, I would, this is what I prefer. It could be either a pre-post like Martha said, but the other is getting rid of dupilumab or any of the reasons to suggest using dupilumab in this patient. And then putting them on this expensive, uncommon medication. But if you want to go with, I guess, more commonly used medications, I guess I can make my own pre-posts. Yeah. That's a distinct block you have there. Why don't you look at your, I mean, cause we're kind of running over, why don't you look at your two questions and, you know, with all the comments that we've offered and sort of see whether you can make it free and post, but, you know, quite fair that it's certainly the great majority of people knowing about the medications would clearly come to the same choice as the best choice. And then if they didn't know about the medications, obviously they're shooting in the dark and whether the commentaries inform them to a point where they would agree with the answer. I was just, all this conversation, I think is very, very important to preserve a MAB question. I love the table. I love, you know, I think people stress out about remembering all the things about the various MABs and you've summarized it all here. I think that has value. So, so working through the various kings, I think is very worthwhile. Thank you.

severe asthma

oral corticosteroids

immune modulators

biologics

dupilumab

personalized approach