The Potential Role for GLP-1 Agonists in Asthma Treatment

GLP-1 agonists have been blockbuster medications in diabetes and obesity but they may also have a surprising role in the treatment of asthma. Join the conversation as Katherine Cahill, MD, FAAAAI, discusses how GLP-1 agonists may improve asthma control and reduce airway inflammation.

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Transcript

Rebecca Saff, MD, PhD, FAAAAI 0:12

Hello and welcome to Conversations in the World of Allergy, a podcast produced by the American Academy of Allergy, Asthma & Immunology. I'm your host, Rebecca Saff. I am a board-certified allergist and immunologist and a fellowship director who always enjoys learning more about the exciting field of allergy immunology. Our podcast series will use interviews with thought leaders from the field to keep you up to date on new developments and to review core topics. Today we'll be discussing one of the hottest drugs out there, GLP1 agonists. These are medications that mimic the action of the hormone GLP1 that helps to regulate blood sugar and appetite, and they're approved for the treatment of type 2 diabetes and obesity. For diabetes, they work to increase insulin release and suppress glucagon release when blood sugar is high, which leads to significant improvement in blood sugar control. They also slow stomach emptying and reduce appetite, leading to weight loss. However, as we'll discuss, they seem to have a lot of other effects and are being studied in many different diseases, including asthma. We are pleased to welcome Dr. Katherine Cahill. Dr. Cahill is an associate professor of medicine and the medical director of the Clinical Asthma Research Center at Vanderbilt University Medical Center. Her research is focused on the mechanisms of adult asthma, particularly severe asthma phenotypes, including aspirin exacerbated respiratory disease and obesity associated asthma. And she is pioneering work on the clinical benefit and anti-inflammatory effect of GLP1 agonist and respiratory disease. Dr. Cahill, thank you so much for taking the time to join us today.

Katherine Cahill, MD, FAAAAI 1:36

Rebecca, Dr. Staff, it's a pleasure to be with you.

Rebecca Saff, MD, PhD, FAAAAI 1:39

Perfect. Would you start by telling us a little bit about yourself and include something you like to do outside of medicine?

Katherine Cahill, MD, FAAAAI 1:46

Yeah, absolutely. Well, let's see, I'm a board-certified allergist immunologist. I completed my training in Boston at Brigham Women's Hospital and was there during my early uh faculty days as an instructor and an assistant professor when I had a career development award, really investigating some areas of severe asthma like aspirin exacerbated respiratory disease. And for the last nearly eight years, I've been here in Nashville at Vanderbilt University Medical Center, where I've remained a physician scientist, really interested in the mechanisms of severe asthma, particularly now looking at obesity associated asthma. An interesting sort of fact about myself, I have been commuting to work by bike since my days as a resident and fellow and uh faculty member in Boston. And I have continued to do that here in the South. So if you come come to Nashville, might see me zooming around on my bike as I commute back and forth and get around campus that way.

Rebecca Saff, MD, PhD, FAAAAI 2:49

That's an awesome way to get around. I think it's so much easier than having to get into a car. Absolutely. So why severe asthma? What led to your excitement about studying that?

Katherine Cahill, MD, FAAAAI 3:00

Yeah, no, that's a really good question. So I have to attribute my interest in severe asthma to my exposures I had during fellowship. So I was had the unique opportunity, I think, to train in a center that offered me lots of exposure to severe asthma, both through my allergy immunology as well as my pulmonary critical care colleagues. And you remember, because we were fellows uh together, and that this was a time when our only biologic therapy, you know, available for our patients with severe asthma was omalizumab. And so we were using a ton of, you know, obviously high-dose inhaled corticosteroid and systemic steroid bursts. And it was not uncommon to have patients on chronic oral corticosteroids. And, you know, seeing patients oftentimes quite young, particularly in the context of aspirin-exacerbated respiratory disease, who were limited uh to um use of steroids, um, you know, was really something that that caught my attention during fellowship and you know, it drove my interest in trying to understand can we do something better?

Rebecca Saff, MD, PhD, FAAAAI 4:04

I'm just gonna add, I'm just curious. So you talked about, you know, now we only had one biologic before. Now we have a number of different biologics. Luckily, we have less patients on steroids. So what do you think we're still really looking for in asthma treatment? Where's where are the holes?

Katherine Cahill, MD, FAAAAI 4:20

Yeah, so you know, I think this is this is what gets me excited about sort of the GLP space is, you know, I think while it's very clear that our asthma biologics do wonderful things and are really, really can be transformative for many of our patients, um, there's still residual risk for many of our patients who are actively being treated with a type 2 targeted biologic, meaning, you know, they may go from an exacerbation rate of four or five a year down to one or two, but they're still having um events, you know, these exacerbations relate to their asthma, as well as perhaps quality of life impairments and you know, sort of symptom limitations. In addition, they're they have quite substantial, you know, um therapeutic sort of burden between the biologic and inhalers, etc. Um, and I would say, you know, there's pretty good evidence that some of that residual risk may be because of non-classical type 2 pathways. And currently we have few therapeutics that address non-T2 processes, and really no therapeutics that address metabolic processes that may be contributing to this unresolved risk for these patients. So there's pretty good data that in the context of our severe asthma patients, if they have comorbid obesity, that type 2 biologics still work for those patients, but their residual risk is higher than their lean counterparts, meaning they have more frequent exacerbations still on a on a biologic, and they still have um greater symptom burden and poorer quality of life. Additionally, mechanistically, we think that there are mechanisms related to metabolism, such as like insulin resistance and maybe obesity itself, that contribute to exacerbation risk. And I think that is what at least one thing we are not addressing with all of our current available therapies. So I believe that targeting metabolism, whether it's with a GLP1 or another mechanism, such as maybe perhaps metformin or future therapies, you know, may have a real role, at least for a subgroup of our patients with asthma.

Rebecca Saff, MD, PhD, FAAAAI 6:40

Absolutely. We were talking about GLP1 agonists that, you know, most of us know about them at this point. I think the survey data says that upwards of 20% of American adults have tried them. So, you know, people have an awareness of them and their role in diabetes and in weight loss. But as I mentioned in the introduction, they're being studied in all these other diseases. How do we think these medications might be working outside of just their role in what we know about weight loss and metabolism?

Katherine Cahill, MD, FAAAAI 7:06

Yeah, so this is, you know, a real active area of investigation. I think there's a handful of plausible mechanisms by which these drugs could be working beyond weight loss, beyond improving glycemic control. Um work that my group and a few others are really putting forth is trying to understand how these drugs may directly impact immune cells. So thinking about our T cells, our lymphocytes, our granulocytes, and then some work that I've done has included looking at platelets. So there's um some data that um it that these therapies may augment how immune cells work. When we think about the respiratory tract specifically, there's also data that suggests that these receptors and then therefore the agonists may have direct actions on the airway, um, such as like in the on the smooth muscle, causing bronchorelaxation, and potentially the airway epithelium. Although I'll say that that is a bit controversial at this time. And then, of course, there's these sort sort of more nebulous mechanisms that we think about and get written about in the literature, but I think are hard for us to pinpoint, particularly in current clinical cohort studies, such as like neuroimmune or brain-lung access mechanisms. You highlighted early on that these drugs improve, you know, satiety, delay gastric emptying. And one of the mechanisms by which they do that is actually working in the brain stem to augment um structures or augment signaling there. And we are coming to appreciate that neurologic mechanisms regulate inflammation, whether it's in the skin, also likely in the airway, perhaps in the gut, in many of the diseases we care about. So that's definitely a theoretical mechanism that needs to be explored in the diseases we care about. And then finally, it's the other thing, you know, in the process of weight loss and in the process of improving uh insulin handling, you get these metabolic shifts. And we can think about that on sort of the macro but also the micro level. And so, you know, I think as we think about cells, we know that how the cell is actively metabolizing, specifically in T cells, that changes what the T cell is doing. It sort of licenses or gives the T cell the capacity to act in a certain way that might perhaps release more cytokines that might promote type two inflammation. So perhaps a mechanism of action on those immune cells is is actually that those immune cells are seeing an altered metabolic state, which is therefore altering the function of the T cell. And then on the macro level, um, I have to think, you wonder how these drugs are shifting microbiome. And we know in our space uh that microbiome seems to be important, at least you know, when perhaps promoting early life, you know, risk for the development of some of our allergic um diseases, including asthma. But within that microbiome, that affects metabolism of the foods we're ingesting and can maybe augment like free fatty acid availability, uh, which is also being studied as a potential therapeutic in asthma. So I think we may at the end of the day figure out that there are a plethora of ways by which targeting these pathways lead to improvements or alter immune function and lead to reduced inflammation in the context of asthma and allergic disease.

Rebecca Saff, MD, PhD, FAAAAI 10:52

Do the GLP1 agonists have an effect on microbiome outside of their effect on appetite and changing what people eat? Is there a direct effect on the gut?

Katherine Cahill, MD, FAAAAI 11:02

So I'm not aware of any data yet investigating that piece. I think that's hypothetical at this time.

Rebecca Saff, MD, PhD, FAAAAI 11:11

And then are there GLP1 receptors on the airway epithelium? Are they on immune cells, or is this more an indirect effect?

Katherine Cahill, MD, FAAAAI 11:18

Yeah, so this is this is challenging um on for researchers because the tools to detect the receptor expression are um are somewhat limited and fraught with uh lack of specificity. So GI GLP1 is a peptide. The peptide binds to a G-coupled protein receptor, the GLP1 receptor. G pro G protein coupled receptors are notoriously like um expressed at very low levels. So they're difficult to identify receptor expression in classical sort of RNA sequencing, you know, sort of single cell sequencing data sets. So the absence of a GLP1 receptor may not actually mean it's there. It may mean the tools we have can't actually pick it up because it's expressed at such a low level. So that's number one. Number two, you know, in the immunology space, we use monoclonal antibodies all the time, right? That's uh the basis of our like flow cytometry assays that we use in the lab or even in clinical lab. And uh the antibodies available for the GLP1 receptor are actually quite poor, have a lot of non-specific binding. And so, you know, if you're not careful, you may pick up receptor expression that's actually not there on this cell. So that's that's a limitation. And then the the third major limitation is that um there seems to be some notable species to species differences. So, for example, mice have very high levels of GLP1 receptor expression on the airway epithelium. And in humans, that's actually not been recapitulated very well. And so I would say at present time, most of the literature suggests that the GLP1 receptor may not be present on the respiratory epithelium in humans, but it's definitely there in mice. But you can prove that with a knockout mouse, but you can't really prove that with a knockout human. So it could be that we just our tools we have available are are impairing our ability to detect it at this present time.

Rebecca Saff, MD, PhD, FAAAAI 13:24

And how did you first get interested in GLP1 agonists and asthma? Or how did the field eventually first get interested? What is it more of this association as they were being used more and more in diabetes and obesity? Or how did that come about?

Katherine Cahill, MD, FAAAAI 13:38

Yeah, so for me, it started a decade ago. Uh, it was the fall of 2016. I had the pleasure through work I was actively doing in aspirin exacerbated respiratory disease to attend an NIH seminar that is held annually for the asthma and allergic disease cooperative research center groups. Um, and at that time, my now sort of partner here at Vanderbilt presented the Stokes Peoples, uh, presented data from their preclinical models. So this was, you know, classical mouse allergen challenge models. And they showed that if you pre-treated with a GLP1 receptor agonist, you could actually reduce classical allergen-induced airway inflammation, you know, recruitment of eosinophils, group two innate lymphoid cells, IL-4, 5, and 13 production, mucus, metaplasia, airway hyperresponsiveness. That really caught my attention. And at the time, I was thinking to myself, there must be some way that we could determine whether this has any translational ability. You know, at the time, even then, these medications were pretty widely used for the treatment of type 2 diabetes. The weight loss piece had not yet been approved, and I think it was under study, but it was not yet approved. So it was really patients with type 2 diabetes were getting access to these medications and using them quite broadly. So I brought that idea back to Boston at the time, and uh a then resident junior fellow in the group Dynafor. And the two of us said, man, I think if we went in the electronic health record, we might be able to dig out some evidence to support whether these class of medications is benefiting our patients with type 2 diabetes and comorphid asthma. And so that's really how this all started. How Stokes peoples got interested in this space and decided to throw this drug into their animal models of allergic, you know, airway inflammation. That he'll tell you about is related to his love of basketball and a friend and colleague who's an endocrinologist who said, Hey, these drugs seem to be anti-inflammatory. You should throw them in your mouse models.

Rebecca Saff, MD, PhD, FAAAAI 15:52

That's very interesting. It's good to have friends in different fields because the crosstalk is really fascinating.

Katherine Cahill, MD, FAAAAI 15:57

Absolutely. I think that's been really uh critical to my own ability to navigate this space, is collaborating with some great endocrine metabolism experts.

Rebecca Saff, MD, PhD, FAAAAI 16:09

You're currently heading up a trial looking at the effect of semaglutide in adults with asthma, just who have asthma that's uh still active despite the use of inhaled steroids and kind of looking at its effect on asthma control and airway inflammation. Can you tell us more about the study?

Katherine Cahill, MD, FAAAAI 16:25

Yeah, so this is a single-site randomized controlled trial. It's funded by the NIH, so the National Institutes of Allergy and Infectious Disease are funding this at Vanderbilt. We are um recruiting 100 participants, as you said, who, you know, remain uncontrolled despite at least medium or high dose inhaled corticosteroids. All of them are adults and have to have comorbid obesity, which we define per uh sort of the current FDA label indication for semagliotide, meaning their BMI is greater than 30 or they have a body mass index of greater than 27 with a weight-related comorbidity, such as dyslipidemia, hypertension, etc. We receive drug and matched placebo from Novo Nordisk, the manufacturer of semaglatide, and it's a 24-week intervention study. The participants, once we've confirmed their diagnosis of asthma through either demonstrating bronchodilator response or air hyperresponsiveness to methylcholine and ensure that they are compliant to their background-inhaled corticosteroids and remain uncontrolled through an asthma control questionnaire score. We then randomize them one-to-one. So at the end of the study, we're hoping to have 50 participants on semaglantide, 50 on placebo, and are following them over 24 weeks study period. During the study, the patients dose escalate across time as per the FDA label. So what folks may not be, maybe or may not be familiar with is these medications typically are started at quite low dose. And then every four weeks the dose is escalated, primarily to promote uh tolerance and reduce side effects that come from these medications. And so we're following that protocol. And we are going up to the doses that are currently approved for weight loss. So we will have doses both for diabetes treatment, the typical dose that's used in diabetes, but also the weight loss dose. We're following the patients across time and utilizing that sort of dose escalation to capture endpoints on various doses which have less risk or less less likelihood of having significant weight loss at the time we're capturing some of the endpoints.

Rebecca Saff, MD, PhD, FAAAAI 19:01

And what is the data that we have already that kind of leads you to think that this might make a really big difference in their asthma control?

Katherine Cahill, MD, FAAAAI 19:09

Yeah, so on the preclinical side, I talked a little bit about, right? The sort of in classical allergen as well as viral challenge models, pre-treatment with the GLP1 receptor agonists can attenuate like classical type 2 airway inflammation and all the downstream effects of that. If you apply these therapies in the context of an obese animal model exposed to allergen, not only do you see reductions in type 2 inflammatory processes, but also non-type 2 inflammatory processes, things like the inflammation, like IL1 beta, IL-6, airway neutrophils are suppressed. So those are the preclinical model data. Um, additionally, there's um been data showing that the um treatment with a GLP1 receptor agonist can cause bronchodilation using sort of um uh airway like bronchial ring um studies or muscle muscle extractions. And then on the sort of clinical side, the body of literature is really limited to retrospective observational cohort studies. Um, but these have been done now across multiple cohorts in the US as well as internationally. And the the sort of the consistent finding is that among individuals who have type 2 diabetes and comorbid asthma treated with a GLP-1 receptor agonist, they seem to have reduced asthma exacerbation risk compared to sort of a comparative group that's being managed with other therapies. Um, so it's really the exacerbation risk that seems to be the signal on the human side that we've been best able to capture. What's been interesting in the context of type 2 diabetes is that it doesn't seem that weight, so BMI, both a baseline and weight that sort of changes as they're on a GLP1 receptor agonist, and things like uh eosinophil counts don't seem to uh affect the reduction in asthma exacerbation risk. So it hints that one, that there'll be maybe non-weight related mechanisms by which these therapies are working, and two, that these therapies may sort of surpass the classical T2 high low paradigm that we see in all of our asthma therapies to date.

Rebecca Saff, MD, PhD, FAAAAI 21:33

So we think they're working both in the T2 high patients, but really in this T2 low, you know, T2 low, more what we think of a more of a TH1 perhaps model as well. Perhaps.

Katherine Cahill, MD, FAAAAI 21:45

So the the preclinical model data would suggest that they're active in both in TH2, TH1. What we have on the you know clinical side, I would say at least suggests that like blood ESN will count. May not be the discriminator of identifying who best responds, that you'll see improvement, at least again, in exacerbation rate, whether their EOs are above 300 or below 300. I think we'll have to wait for our sort of prospective study to really answer the question of whether sort of T2 state by our classical biomarkers such as blood EOs or XL nitric oxide level are relevant in therapeutic response to GLP1 receptor agonists. What we do know is that patients with obesity and asthma tend to have lower T2 biomarkers than their lean counterparts. So using blood EOs, pheno for this patient population, they say they tend to be lower, um, may not be absent, but tend to be lower in total compared to lean counterparts. So it does there's you know suggest that somebody with obesity with asthma is more likely to have some non-T2 mechanisms at play, or maybe non, you know, non-T2 or T2 low sort of phenotype. But the association between benefit and T2-ness, I think is is definitely unknown at this point.

Rebecca Saff, MD, PhD, FAAAAI 23:21

Yeah. It's interesting that you say that it what you're really seeing is that it reduces asthma exacerbations because you would think, particularly with weight loss, you would also see just overall improved airway function. And so that's certainly probably a piece of it. But the asthma exacerbations is a little bit more express surprising.

Katherine Cahill, MD, FAAAAI 23:37

Yeah, so there have been some small sort of uh prospective studies, like looking at lung function in a cohort of diabetics without asthma and sort of modest improvements in lung function. Certainly, the mechanisms by which these drugs are expected to work suggests that we would see improvement in lung function. I think the challenge is when you're using electronic health record data, lung function data is pretty messy. It's a lot easier to sort of identify when someone's had an exacerbation than to meticulously track sort of FUB1 values across time, particularly when we may not consider, like, are we withholding medications like bronchodilators, you know, that we would carefully control for in a clinical trial? So I think the good news is in our study, we will have pretty good data on lung function, at least in our cohort.

Rebecca Saff, MD, PhD, FAAAAI 24:32

And then these are medications that maybe as allergy immunology physicians were not as comfortable prescribing. What are the kinds of counseling that you would give to a patient, side effects to look for? I know you mentioned the kind of need to taper up slowly, nausea, GI side effects. What do you counsel them?

Katherine Cahill, MD, FAAAAI 24:49

Yeah, so it is the GI side effects that require the most counseling. I always counsel patients to say, you know, be very cautious as you're eating as you first start on these medications because everyone responds differently. Um, about 40% of patients in the phase three studies that led to the approval of the use of these therapies in weight loss or for weight loss reported GI side effects: nausea, vomiting, abdominal pain, diarrhea, you know, burping, a variety of GI side effects. And so, but it also means that about 60% didn't report them during the study. So you're not guaranteed that you'll have these side effects, but I always cautious, like every person seems to respond differently, and you just need to be careful as you're you're starting on the therapy, particularly the first few doses of each dose increase. It does seem that as patients um are stabilized on the dose, the side effect profile seems to improve. But I do think that there are a number of behavioral factors that may dictate the type of side effects a patient experiences. So someone um they kind of need to relearn how to eat, meaning small, um, maybe more frequent portions. Um, if they were a binge eater, that might be uh really uh challenging for the patient. They may find that they are actually full before their body perceives they're full. And so they overeat, and that really drives some of the nausea and the vomiting. Um, additionally, in talking with patients, it seems like choices of food, particularly beverage, like carbonated beverages and things like alcohol, um, may magnify some of the side effects. So I really cautious patient, caution patients as they're starting, like just be careful, take things slow, stop before you you notice your full, consider not just portion control, but also um consider maybe more frequent eating, maybe akin to when they're if they're female, when when they were pregnant. Um, because that sort of small frequent eating may actually do better for them, those sort of large meals once or twice a day.

Rebecca Saff, MD, PhD, FAAAAI 27:10

Besides the side effects, are there safety considerations that people need to be aware of?

Katherine Cahill, MD, FAAAAI 27:15

Yeah, I mean, so the the biggest safety consideration is um, or actually contraindication is medullary thyroid cancer. So um fortunately that's a fairly rare condition. But there are known, you know, clinical syndromes like M E N one and two associated with it. Um, and if they have a personal or family history, they should be um cautioned against using this therapeutic class. And then of course, anyone that has experienced an allergic reaction to a medication in this class, you know, that should be cautioned on on not using um the class of medications going forward. Outside of that, you know, I think the side effects that are more serious mostly relate to the GI processes and the rapid weight loss that can be seen. Remember, 70% of the patients in the clinical trials were female. I think probably if uh you look at the data of who's used these in the US population to date, it's overwhelmingly female. One of the things that females sort of already have a predisposition to, and then in the context of OBC have an increased predisposition to are things like gallstones. Um, so colothiasis, colcestitis, um are definitely things that you have to be um aware may happen. Rapid weight loss itself can bring on an event like that. And so, you know, that's cautionary. So certainly you want to inform patients not to ignore abdominal pain type symptoms um and maybe even you know nausea, vomiting that might be attributed, oh, it's just the drug, but it actually could be a more significant side effect. So I think that's one thing that we don't usually talk about with our typical asthma or allergy patient. You know, and I think on the extreme side, you know, weight loss can be quite significant for patients. And so things like underweight or malnutrition, like you know, insufficient caloric intake leading to malnutrition, you know, are things also to just keep in mind if you have patients on these therapies, you make sure that they're they're not losing so much weight too fast and in a way that would um you know impact other disease states um and perhaps cause new problems.

Rebecca Saff, MD, PhD, FAAAAI 29:39

You mentioned you know Stokes' model where he was seeing decreased allergen reactivity. Are you looking at you know skin testing data or anything like that with this group of patients? Or are there ongoing studies that are looking at kind of allergen reactivity or kind of, I know that you said the TH2 markers aren't as prominent, but it sounds like there is some effect.

Katherine Cahill, MD, FAAAAI 29:59

Yeah. So in the context of our study, we're not uh looking at, you know, of doing objective skin testing measures or change in reactivity or serum-specific IgE levels across time. It was just a bit beyond the scope of um our budget, frankly, uh to be able to do. But I will say, you know, many of the patients who have asthma with comorbid obesity are actually atopic or report a history of atopy. And we are we are capturing that. So we'll know, you know, if the patient reports, if they've had testing done, what the testing results were. Um, so that's you know, not as ideal as doing uh objective testing and measuring the testing across time, but we'll have some measure of, you know, maybe atopic status, whether that impacts response to therapy or not. Um, we're also capturing some symptom scores. So we're doing some upper airway symptom scores that might hint at whether there might be any improvement in things like allergic rhinitis or chronic sinus disease. One of the things that has actually surprised me, you know, just enrolling these patients, there's a lot of chronic rhinosinusitis comorbidity, which we know is often comorbid with severe asthma, but I was somewhat surprised in this obesity population to see such high burden of CRS. And so we may have some indication from just symptom scores that these therapies either work better or different based on CRS comorbidity and or may influence um CRS symptoms across time.

Rebecca Saff, MD, PhD, FAAAAI 31:35

So we'll know who better to target with these medicines. If they're a patient with asthma and CRS, maybe they're even more likely to benefit from these medications. Maybe, maybe. And then this is this is just one of kind of many metabolic medications that are being developed. Do you think there are other medications on the horizon that would benefit allergic disease despite being really more targeted at metabolism?

Katherine Cahill, MD, FAAAAI 31:59

Yeah, so you know, I think it's important we talk about a couple things. Um, first, let's let's talk about metformin. So, you know, again, another sort of broad um metabolically active therapy, widely used for type 2 diabetes, um even in prediabetes, you know, PCOS, it's often reached for. Just like GLP1s, there are observational cohort data which supports that treatment with metformin among patients with type 2 diabetes and comorphid asthma reduces asthma exacerbation risk. This data has led a group at Johns Hopkins and Baylor. So it's led by Meredith McCormick at Hopkins and David Wu at Baylor to do a prospective study with metformin. That study is ongoing, actively enrolling. And we sort of anticipate both of our studies may wrap up and read out about the same time. So we may have some similar data, prospective data, on the use of metformin in individuals with asthma and comorbid obesity. Um, of course, metformin is a really old medication, and the but there's a lot of newer therapies in development in both the diabetes and obesity space, um, which may have a role in asthma and allergic disease, particularly if we find positive signals from our GLP1 study. So certainly um in our study we're using semaglantide. Cemaglide is just a GLP1 receptor agonist, but we already have dual GLP1 GIP receptor agonists on the market. That would be pterasepittide, so that's fully approved for type 2 diabetes and weight loss. Multiple other dual GLP, GIP1 receptor agonists are actually in um in development in phase two studies. And a study of a novel GLP1, GIP receptor agonist just opened up in asthma, a phase two study. So that's ongoing now as well. But that's just the start. There are triple combination therapies and then other dual combination therapies that are out there and show really dramatic benefits with weight reduction and um therefore maybe leverage certainly for an obese asthma patient population to bring about weight loss, but also may have some unique mechanisms of action that we haven't even yet explored. So these are therapies like GIP, GLP, glucagon receptor combo therapies, and then there's even amylin agonists and a few others. So all these can be kind of used in combination for various disease states. And really, the pharmaceutical companies are doing a ton of development in this space. I think we'll first see them come out and be available for weight loss, but they're also now moving directly to more inflammatory conditions, particularly conditions that are associated with obesity.

Rebecca Saff, MD, PhD, FAAAAI 35:12

I know that they're being used in neuromethylagic diseases. I actually have a friend in who says they're being used in patients with substance abuse issues, that it helps to decrease that drive to use, which is incredible, that you could have a medication to do that. So I think we're gonna see them in all these different spaces and how they interact with other medications that we use, whether it's our TH2 biologics, that I think is gonna be fascinating.

Katherine Cahill, MD, FAAAAI 35:36

No, it is. And you know, I think what this space has informed me as a clinician, even if I'm not doing research in this space, but just thinking about the comorbidity that our patients have beyond asthma and allergic disease. And we, you know, we know that many of our severe asthma patients have sinusitis, may have nasal polyps, may have EOE, may have chronic urticaria, you know, certainly maybe atopic, right, with allergic rhinitis. You know, if they're a younger group, they may also have food allergy, unfortunately, right? And so we're used to the that comorbidity or that, you know, sort of multimorbidity in our patient population. But fortunately for most of those patients, you know, some of our T2 targeted biologics address all of them. Um, but what we often don't think about is the cardiovascular disease, the chronic kidney disease, right, the substance use issues, the depression and anxiety that these patients have, the sleep apnea and reflux, which we know, you know, can can contribute to uncontrolled asthma, you know, these GLP one-receptor agonists and the sort of incretin, the whole incretin space, you know, may have actions targeting all of these pieces, um, which I think would be really, really novel and just really valuable to our patients.

Rebecca Saff, MD, PhD, FAAAAI 36:54

So when is your study likely to read out?

Katherine Cahill, MD, FAAAAI 36:59

So I'm really hoping if we can enroll the last few participants, that we would have data to present at AAA AI in 2027. That's our goal. And um, I think the the rate limiting step is the wide use of these therapies out in the community and the lack of interest of being in a placebo-controlled study. So we'll see how the first part here of 2026 goes for us. But hopefully we will be able to read out in hopefully February, early March of 2027.

Rebecca Saff, MD, PhD, FAAAAI 37:35

Well, we will look forward to the data because I think this is going to be a really exciting direction for asthma therapy to go. Are there any other take-home points that you really want to make sure that people take away from this?

Katherine Cahill, MD, FAAAAI 37:47

Yeah, I mean, I think the one thing that we've talked around, but maybe haven't talked specifically about is, you know, there's pretty good data that if you can get your patient with severe asthma who has obesity to lose weight, particularly 10% of their body weight or more, their asthma is going to be better. So, you know, I am working under the assumption that the at the worst case scenario is that this group of medications can facilitate our patients with asthma and comorbid obesity to lose that sort of weight that would is associated with improved asthma outcomes. So that's like the worst case scenario, right? They lose weight and their asthma gets better. Their control improves, maybe their exacerbation risk goes down. Though, of course, even you know, not everyone loses that amount of weight on these therapies. So it's not like this is gonna still address you know obesity for all of our patients, but I think for a fairly significant majority of patients, um, it could really be instrumental in bringing about that weight loss that we know is gonna bring about improvement and our asthma outcomes. You know, what we're hoping to do in our study is say above and beyond the weight loss, these drugs have direct airway or anti-inflammatory actions, that might mean that they're beneficial even if you don't have 10% of your body weight to reduce, right? And um, so I think as the future of this space is really gonna hinge on is it just the weight loss? Or are these therapies working in more direct anti-inflammatory ways that are leading to, say, the improvements that we might see in the lung or you know, might see in the joints in the context of rheumatolotic disease or in the skin, in the context of psoriasis, which is associated with obesity and other things.

Rebecca Saff, MD, PhD, FAAAAI 39:44

I hadn't heard of the lung brain axis before. Certainly, I think we're all familiar with the gut brain axis at this point, but I think that's amazing. It's amazing how much of uh kind of our responsiveness is controlled in our brain, even in places like our lung, where we think maybe it's more, it's it's more separate. So it's an interesting interplay between all the different um the nervous system and the skin and the lung and the gut.

Katherine Cahill, MD, FAAAAI 40:09

So yeah, and what I I guess I didn't also mention the sort of gut-lung access, which is another area, right? So that microbiome, metabolites, right, um, actions in the in the gut that influence the airway as well. I think as we move, you know, look ahead the next decades of sort of research and science and medical advancement, I think it's going to be this integration back to the whole body. I feel like for the last few decades, we've been spent focusing on sort of our own, you know, organ system, sort of working in silo. It's you know, our favorite cells, um, and but fail to recognize that, you know, are the patients we treat are whole bodies that are are interacting and the the brain is influencing what's going on in the rest of the body. Um so I think it's an exciting space because we may finally have tools to be able to tease that out in humans, where our counterparts who do the preclinical models are really have been advancing that even for sort of faster because of the ability to work in knockout mouse systems, et cetera.

Rebecca Saff, MD, PhD, FAAAAI 41:14

Well, this is fantastic. Thank you so much. We're excited to see the data eventually play out and uh continue to teach us how to treat asthma better. Absolutely. Thanks, Rebecca. So guys to meet with you today and discuss this topic. We hope you enjoyed listening to today's episode. Please visit aaaai.org for show notes and any pertinent links from today's conversation. As a reminder, this podcast is not intended to provide any individual medical advice to our listeners. We do hope that our conversations provide evidence-based information. Any questions pertaining to one's own health should always be discussed with their own personal physician. The Find an Allergist Search Engine on the Academy website is a useful tool to locate a listing of board certified allergists in your area. Use of this audio program is subject to the American Academy of Allergy, Asthma & Immunology Terms of Use Agreement, which you can find at their website. If you like the show, please take a moment to rate and subscribe to wherever you download your podcasts. Thank you again for listening.