General Updates on asthma in clinical research for IQVIA colleagues.

Welcome everyone. Today we will be tackling asthma, and brace yourselves because if you thought that you knew asthma, well, you might just see that it has been turned upside down. Because while asthma before used to be a condition that was a one-size-fits-all, that's an old notion. All the ideas that we had before, we have been now exploring that asthma is perhaps a spectrum of different conditions that just happen to look similar on the surface. This shift in thinking is completely changing the game for how we treat it. And that could explain why when you get RFPs or protocols, you're starting to see, well, words and bucket lists of inclusion criteria that we were not familiar with before. I mean, I'm an asthmatic and this has all been an exciting time for us. So let's dive in. When we start with the scale of this, there are hundreds of millions of people globally that have asthma. Just think about that for a moment. It's one of the most chronic, common diseases out there and it affects many lives and many families and co-workers even. But here's the central mystery: if so many people have asthma, Why is it that my asthma can be so wildly different from yours or our friend or coworker or neighbor? One person gets it from exercise, the other person gets it from cold, somebody else gets it from allergies, and sometimes there is no obvious trigger. So this question has been a puzzle for a long time and we're finally starting to get some real answers. And those answers are leading to what could be a personalized medicine. Here's our roadmap for today. We'll start with a real patient case. We're gonna ground these concepts with Jane. Then we're gonna dive into the new language of asthma, how we've evolved from seeing it as one disease to recognizing distinct endotype. That's your first keyword. We'll explore the deep pathophysiology interleukins, maybe we'll choose one, IL-5. We're going to also look at various devices and biologics. And then we're going to wrap up with some clinical trial considerations on what's coming next. So let's start with the definition. So what exactly is asthma? It's a heterogeneous disease and it means it's not just one thing. It's characterized by chronic airway inflammation. Keep that in mind, that inflammation is key. It does define symptoms like wheezes, shortness of breath, chest tightness. Most people call it chest pain, but it really isn't pain, it's cough and chest tightness. Cough is the most common symptom of asthma. These symptoms can vary over time and vary in intensity and even airway limitation. And that variability is crucial to understand why asthma patients present differently. So the first thing we're going to do is talk about Jane. So who is she? She's 48 years young. She's 5 foot, feet 5 and 142 pounds. And she's really illustrating the complexity of what we're dealing with because she's referred to, let's say, me after her third hospitalization this year. Despite being on medium-dose inhaled corticosteroid, ICS, long-acting beta agonist, LABA, montelucas, and even intranasal fluticasone because she has chronic rhinosinusitis and nasal polyps. You know, she even had two polypectomies already. She's using oral steroids 7 months out of the year. I have no idea how she looks fit on this picture. Maybe it's an old picture. She does use her rescue inhaler daily and she wakes up twice a week from her asthma at night. No allergies though, which is very interesting. Looking at Jane tests on the right, you can find that her lung function is really compromised with an FEV1 at 46% predicted. Her exhaled fraction of nitric oxide is elevated at 55 particles PPB, and it suggests significant airway inflammation. Her IgE is high at 500, but interestingly, she is negative for specific allergens. And that blood eosinophil count at 500 cells per microliter Well, that's telling us there is significant type 2 inflammation happening. Oof, type 2 inflammation, I heard that before, I don't know what that is. So the CT scan, as you can see, it's starting to show the damage right here, some airway remodeling. What's black is air and what's white is non-air. And along the lines that you see in the black, those are veins coursing the lung in normal. On the right, it's Jane's, and you can start to see that we're seeing lines that are so different from the normal that we need to see, and those are airways. That means there's some changes that are happening. We call them remodeling. If we were— not that we're going to— but if we were to do a biopsy, that really tells the story. You can start to see some mucus plugs. You can start to see muscle hypertrophy, the thickening of the muscle surrounding the airways. You start to see goblet cell hyperplasia. What's goblet cells? Those are the cells in our bronchial tubes that make mucus. And if there's hyperplasia, that means that they are starting to work extra or overtime. You also start to see a ton of eosinophils in the sputum. That is what severe, uncontrolled eosinophilic asthma looks like under the microscope. I threw at you some words now: eosinophilic asthma, T2 inflammation, eosinophils, pheno, IgE. All of these things are now what we use to separate one asthma from the other. And that's what's really driving someone's asthma. If we look at the evolution of asthma terminology, it's really important to know what our language around asthma has evolved to be. The traditional view is that it was just one condition, one homogeneous condition. And then came the Th2 concept, and that focused on the lymphocyte T helper, Th, T helper type 2 cells. But that was limited because there are some other ILC2 cells. Th2 T helper cells, those are our reactive immunity. Because those T helper cells modify themselves, activate things in response to a trigger. But we also have some other cells. Those are called innate immunity. They don't really change, they just know that there's the first frontline defense. Because they were all of these type 2 cells, TH2 cells, ILC2 cells, we now call it type 2 immunity. Type 2 inflammation rather than Th2 inflammation. So now, Type 2 inflammation captures both adaptive and innate immunity. And now we recognize distinct endotypes— here's that word again— Type 2 versus non-Type 2 asthma. Completely different biological mechanisms. This is not just words. It really is paving the way for truly personalized medicine. So what's type 2 inflammation? Well, type 2 inflammation is the engine behind most asthma. We're talking about 50 to 70% of cases. It's not just affecting the lungs either. It drives conditions like atopic dermatitis, eczema, chronic rhinosinusitis, nasal polyps, allergic rhinitis, even eosinophilic esophagitis. You're starting to see these indications that we are getting in our RFPs, and those indications are all part of the same umbrella but very personalized. Now we know that there is that T2 inflammation that is underpinning all of these things. And understanding these connections, it's huge, because if you work for a sponsor, then that means that molecule can actually be tested in various trials in different indications. We can potentially target the root inflammation causing multiple problems for any patient. It is that holistic care that we all strive to get. It's not just individual symptoms. Let's talk about this endotype and the phenotype. What's the difference between them? Well, If you remember one thing from this presentation, make it this: phenotype versus endotype. Think of the phenotype as the what. What you see. You see a red car. You see an asthmatic. That is the phenotype. It's allergic asthma. It's exercise-induced asthma. It's cold-induced asthma. Late-onset asthma. Reflux-induced asthma. That's what you see. The endotype is the why. It's like knowing whether the red car has an electric engine or a gas engine. That's the specific biological mechanism. So now you know, because T2 inflammation, T2 high, that's the endotype. And under that T2 endotype, we need to find out Which of the interleukins are elevated? Is it IL-5? Is it IL-4? Is it IL-13? Is it IgE, which are immunoglobulin E? Is it eosinophils? So these are the drivers of the endotype T2 asthma. What about the non-T2 asthma? If there is T2, there is non-T2. Well, that's the asthma that is driven by neutrophils, not Eosinophils. This one doesn't respond well to steroids. You've known those asthmatics around your friends or neighbors. Frankly, it is still a big challenge for us and we still need to do— we're starting to see a lot more trials in non-T2 asthma. Talking about key biomarkers, so if we need to know the endotype, how do we figure this out? This is where biomarkers come in. They're like clues that inflammation leaves behind. Blood eosinophil count, 150 cells per microliter, suggests a type 2. Even over 300 suggests type 2. Over 300, we know that we need to go for biologics. A FeNo, that's a breath test measuring airway inflammation. Over 50 ppb particles per— over 50 ppb in someone not on steroids, that's high. Serum IgE helps identify allergic triggers. The key is using these together to build a complete picture. This is where we see all of these start to give us buckets. Of this asthma. To the left upper, this is the phenotype evaluation: spirometry, asthma control, asthma symptoms, allergies, asthma history, family history of allergies, GERD or gastroesophageal reflux, sinus disease, obesity. On the right, you have the biomarkers, Those are the IgE, the skin prick test for allergies, the complete blood count of eosinophils. We looked at sputum eosinophils. It wasn't as stable as a blood test. Fraction of exhaled nitric oxide or FeNo. Based on these two, we can come down and now organize our asthmatics, at least for now, into these buckets. Severe allergic phenotype, and you can see there's IgE there, IL-4, IL-13, IL-4 receptor, and those can be treated with biologics like dupilumab, like omalizumab. The second one is the severe phenotype, eosinophilic phenotype. You start to see the same ILs, but it's mostly high eosinophils, and those respond better to IL-5, IL-5 receptor, dupilumab as well, mepolizumab, reslizumab, etc., benralizumab. Looking at the asthma with physiologic impairments where you see most smooth muscles— smooth muscles use a signaling inside those smooth muscles called acetylcholine. Those are the asthmatics that respond to long-acting anticholinergics or antimuscarinics, LAMAs. Those are also the ones that respond to a procedure called thermoplasty. We'll talk about it in a minute. And then you have the non-T2 severe neutrophilic phenotype. Those are the ones that mostly have neutrophils that respond to IL-6, IL-8, and you start to see that mostly antibiotics such as macrolides or doxycycline are given to those patients on the long term to reduce the exacerbations. You're starting to see how phenotype and endotype can really give us to understand why certain asthmatics are still symptomatic and are still providing exacerbations and hospitalizations. Those are the key biomarkers that we discussed, and these are the clinical utility of these type 2 biomarkers that we also discussed. As we said, 50 to 70% of of asthma is driven by type 2. And those are, as you can see, driven by these various interleukins. Now, somebody might say, why don't you just give them steroids? Well, steroids have a lot of side effects— hypertension, cataracts, diabetes, brittle bones or osteoporosis, and so on and so forth. Therefore, steroids help because they actually knock down all of these and even cellular immunity. We don't want to do that. We want to actually have smart bombs that go directly without any collateral to just lower that which is elevated. Does that mean we cannot give them, for example, inhaled corticosteroids? We can. There is a clever trick for that. Is when you look at the high exhaled fraction of nitric oxide, you have to increase the inhaled steroids to a higher dose, add LABA, add LAMA, and then if that's If the disease still remains uncontrolled, we move to biologics, and the choice of those biologics will depend exactly on these interleukins you see here. Now, how do we determine specifically, again, each of these interleukins give us a specific phenotype of asthma. But it's not just that. It also gives us a specific on other conditions. And those conditions would be— we've already looked at them as the phenotype— which are chronic rhinosinusitis, allergic rhinitis, and so on. And those will also fall under asthma phenotypes that would be candidates for biologics. Initially, we're going to talk about one of those interleukin types, such as the IL-5. What does IL-5 mean and where does it come from? This is where it gets really interesting. We used to think that IL-5 was just about eosinophils, but emerging evidence showed that IL-5 receptors are on multiple cell types that are ciliated, epithelial, fibroblasts for scar tissue, plasma cells that make antibodies, mast cells that degranulate, and our response to allergy. So IL-5 is already orchestrating a multi-front attack. It weakens the protective airway lining. It makes the mucus thicker. It makes the mucus stickier. It leads to these awful plugs that make people breathe with difficulty and have this mucus that needs to be cleared through cough all the time. It drives long-term airway remodeling. So it's not just inflammation, it's potentially driving permanent damage. IL-5-driven airway remodeling means that you have to think of a healthy airway like a smooth pipe. The IL-5-mediated damage starts roughing up the lining and making it leaky. That's why you still— you start to have, you know, how when you have drippy nose That's because the mucosa starts to become leaky from inflammation. Then the IL-5 activates the cells that lay down the scar tissue, thicken the muscle, increase the mucous gland. And over time you start to get structural changes. Thicker walls, more smooth muscle. It's like the more you activate the muscle, the more like someone goes to the gym and becomes like a bodybuilder. They sound like they are strong, but they're inflexible and they cannot move very easily. So your bronchial tubes don't move very easily. And then the basement membrane starts to get scarred. What's the clinical consequence? Potentially irreversible airway obstruction. Guess what? Asthmatics eventually over time become obstructive COPD, but not because of smoking, because of this chronic inflammation. That's why these— some patients have persistent breathing problem even between the attacks. Here's something. Even with anti-inflammation, and we're starting to see that there is this permanent damage, what does it mean for the patients if we were to actually have a microscope and look further? This is where it gets interesting. This is actually here and now in 2025. 2025, moving to 2026, we're going to start to see this come into exploratory endpoints in the RFPs that we get. And that is the remodeling of the IL-5-driven inflammation starts to cause something which is small airways. Small airway damage is what we call the silent zone of the lungs. Think about it for a little bit. If you look at the right of our slide, you'll see the large airways, more than 2 millimeters, have cartilage in them which keeps them open. As that diameter starts to come down slower, smaller and smaller, we get to the small airway, less than 2 millimeters, the bronchioles, terminal bronchioles, respiratory bronchioles, and even alveolar ducts before we reach the air sacs or alveoli. Those small airways do not have cartilage to keep them open, so they collapse on themselves. Have you ever felt that you had tightness in your chest, like you couldn't— like there's air inside? Well, if you take a deep breath in and and exhale only to halfway and then breathe from there in and out. That's what patients with air trapping in their small airways feel like. Sometimes when you take a deep breath, if you had a stethoscope, I used to play this. I would put a stethoscope on my lungs and only one of my ears would have it, the other one is to the ambient air and I I would take a deep breath in and exhale. My mouth stops exhaling, but my stethoscope still hears the air moving in my lungs. That means that there's air that's still in small airways evacuating. That's called prolonged expiratory phase. Very, very interesting. Well, we're starting to identify that. This is some symptoms that fall under the radar, and this is a major contributor to breathing difficulties because of long-term inflammation causing damage. Now, standard spirometry gives you the first, second FEV1. It gives you FVC even 6 seconds. But does it give you the entire vital capacity or the entire total lung capacity? We don't really pay attention to that until we start to do, and that's when we call the silent zone, because so much disease activity can be happening completely under the radar. How did we even think about that? Well, the histology shows that fibrosis happens even with patients with minimal symptoms. And then when we look at the CAT scan, this is interesting. We already talked about what a CAT scan looks like. This is like a bread slice of our chest. When you are in a CAT scan, you are on a, um, stretcher that goes inside that donut, right? So the donut slices the person, if you will, metaphorically. And we see two colors. The black is the air, the white is non-air. The black is the air means that these are the lungs, and we already talked about these lines in here, those are the veins coursing through the lung. Between, you start to see white, that's the heart forming in between the lungs, and here it's the aorta, if you want to know. But what is this thing that's circle? That's black. Black is air. Hmm, what is circular between the lungs? The trachea, the windpipe. So this is the windpipe between the two lungs, and you see that it's smooth, same color, except this is in inhalation. And then when we tell the patient to exhale, we call that dynamic CT. When you exhale, guess what? We start to see two colors. There's a little bit of a blush here and there's black. The black is air, so that means air is trapped in those areas, and that's how we identified that there is indeed small airway disease in those areas causing air trapping. Fascinating, isn't it? We're starting to know what's happening in those lungs beyond the spirometry. Spirometry is just function. We're now looking at a function but differently, something that the naked eye couldn't see before. Now, these are all conditions associated with small airway disease. We're starting to see airway muscle hypertrophy, remodeling, and scar tissue. This is to show that in fact imaging helps us indeed. And you'll— that's why you see me always in the medical consideration trying to push the sponsors to try to include CT densitometry and AI looking at these CT densitometry to start to look at patterns that would help us figure out these things so we can sub-stratify those groups of patients. So if we end up with a negative trial, could we find out if maybe a substrate of patients would have been a better candidate for that IMP rather than just saying another trial that didn't work in asthma? Looking at the GINA guidelines, the GINA guidelines are what regulates the guidelines in terms of treatments and diagnostics and in asthma. These are the foundational guidelines, and in order for us to understand what to look for, first of all, let's define what we're talking about. Therapeutically, you have the maintenance, you have the relievers— when you— I have extra symptom, how— what can I do in order for me to feel better? And then you have add-on therapies such as the biologics or the thermoplasty, etc. So let's delve into this further. This is one slide. This is not all about treatments. I wanted to give you ideas so that you understand what these words— when it comes to asthma trials, how to understand them. In the GINA guidelines, you see the circle. It's Assess, adjust, review. Assess, adjust, review. You have an escalation. First, you start with low-dose inhaled corticosteroids, and then inhaled corticosteroids with maybe formoterol. And then you go into step 3. You add formoterol, which is a long-term LABA, along with low-dose maintenance, and you start to add the dosage of you crank up the dose of the steroids and the LABA until at some point in step 5 you can add LAMA. And then in terms of adding something else, you can add a reliever. But we used to use a reliever, the Ventolin, the old-fashioned SABA, short-acting, meaning it has a rapid onset. If I use it, I want to feel it immediately. I don't want to wait long-acting. I want to have short-acting. So it needs to happen right away. It's almost like you have a heartburn. Do you really want to take the purple pill? It's going to take a while to work. Even though it stays longer, it takes a while to happen. So that's a maintenance. I want maybe Tums to take, or, um, Mylanta or Gaviscon, any of those that are immediate-acting, that makes me feel relief immediately. Here's the new kicker in 2025. We no longer use just beta-2 agonists. We use beta-2 agonists and inhaled corticosteroids. We pulmonologists used to do that off-label because we noticed that it helped. It took trials to make that safe for GINA guidelines to now have inhaled corticosteroids plus a SABA in order to be the reliever on top of the maintenance. Why is the maintenance important? Because just because you feel better doesn't mean you can stop your insulin. You need to have the long-acting insulin and then you have to have the short-acting insulin for when you eat. Something similar. Now, When I give inhalers to my patients, I tell them in 2025 inhalers have a first name and a last name. The first name is the medication— Formoterol, Budesonide. The last name is the actual device inhaler. They're not all the same. Some of them are propellers that you have to really exert a lot of inhale force to pull the medicine out of the propeller, into your mouth, across your voice box, down your trachea, split into two, all the way into your lungs, front and back, up and down, right and left. You can tell that not all these inhalers are the same. So to the left, you can start to see that there is— this one is called an MDI, that's the one we know. With the correct technique, 20% of the aerosol reaches the lungs. Show of hands, who here thought that the entire medicine that you get from inhaler reaches your lung? Turns out you lose 80% in this distance. And then it's air, so it's a liquid that goes where the path of least resistance. But I need them in where there's more more resistance to open up those bronchial tubes, that's not where it's gonna go. So that 20% only with good technique. The next one to the right is a soft mist inhaler. That one is a mist. It mixes with your lungs and it's easier for people that have difficulty taking a deep breath in. And then you have the dry powder inhaler. Show of hands, who thought dry powder inhaler is only one type? Nope, we have several. We have the Diskhaler, we have the Handihaler, we have the Turbohaler, and so on and so forth. You will have the PressAir. So I want you to know each one of them has a different need for a pressure to pull the medicine out of it. How do we know, and why is it important? Because if you're a CRA and you're going to those sites, you want to make sure that your coordinators, your PIs, are communicating to the patients how they choose an inhaler. And if we are designing a manual with the sponsor, we need to make sure that they include how to choose an inhaler and how to do the proper techniques of the inhaler. So the device selection is is crucial in order for that medicine to get into the lungs. What are the errors of use of inhalers? In the MDIs, it's poor coordination. You have elderly or arthritic people that perhaps by the time they press, they take a breath before they press, or as they press. So they may not necessarily coordinate it. We used to have a game where we would bring those rubber bands and we would literally make the hands into a rubber band so you couldn't move the hand. And now you get the inhaler and try to use it. It was laughable, but not for people with arthritic hands. Coordination is a big deal. There's an inadequate speed or depth of inhalation. There's no breath hold. When you actually do an inhale, you have to hold your breath. Why? If you had an air freshener and you misted it in the air, those molecules don't drop to the floor. They hang in the air, right? That's what you want for an air freshener. But for an inhaler, you want them to drop to the floor, which is the lungs. So you have to hold your breath and not start speaking or laughing or talking until maybe about 10 seconds for those, um, droplets to fall into the lungs. What about dry powder inhaler? Incorrect preparation. What's a preparation? Well, you have to pull the capsule out of the box, put it in the device close the device, puncture it with the needle that's inside by pressing the button, and then inhale. If you didn't do it this way, you're not going to get a dry powder inhaler. Or you don't empty your lungs before you take the next inhale, so it's not deep enough. And then the other one, which is no breath hold. How do we choose that inhaler? Well, we need to know our patient's ability to have a lung power to extract that medicine from that particular propeller or inhaler. You can see the particles that are needed in order to penetrate the lung. They need to be super, super small. So they put them in various ways, either in a lipid molecule or a nanoparticle or There's a variety of ways that these technologies happen. And so when you're talking about the inhalers, well, each inhaler has a power to specifically be able to pull from there. This is the soft mist inhaler. You turn it and that just mists the air and you can breathe it in. And the dry powder inhaler, this is the resistance It's literally like sucking something out of a straw. If you've ever had a thick milkshake and you're trying to suck it through a small straw, you start to fight with the person that handed you this straw. Why did you give me a straw for a thin liquid? This— I need a bigger straw. That's how it feels like to pull these medicines out of the inhaler. We have this device. I used to have it for all my sites that is called the in-dial check, and it measures the person's ability to have what we call the peak inspiratory flow rate. The magic number is 60 or greater. That gets you most of the inhaler. If it's less than 60, you have to look at your patients whether they might need a nebulizer or they might need the mist. What is the correct inhaler use? If it's an MDI like Ventolin, you have to do a slow and steady. Empty your lungs, put the inhaler in, press, The soft mist inhaler, same thing, slow and steady. If it's a dry powder inhaler, it's the complete opposite, hard and fast. Many of you are thinking, hold on a second, they have more than one inhaler. They have an inhaler that's the maintenance one with the triple combo, that's a dry powder inhaler, that's hard and fast. But then the Ventolin, which is the rescue inhaler, that's slow and steady. Exactly. Patients don't know that if you don't repeat that. Why do they make this complicated? I don't know. I've been in this 15 years. Trust me, this is what they— these people. So if you have Any parent, loved one that have inhalers, take this to them and teach them how to properly do the inhaler. Nebulizer, neither. You need to just breathe in and out slowly like you're breathing normally because it mixes with your breath. Now we talked about all of those inhalers, we talked about nebulizers, we talked about the, the relievers, but we didn't talk about the ones that have that hypertrophy of the muscle. What does it look like? Well, if you see the— direct your attention to the right lower area. Healthy airways have this very dark red circle. That's the smooth muscle. It's very thin. It doesn't crowd the inside of the airway. With asthma, you start to see it thicken out because of all we saw— the chronic inflammation, the in and out, in and out contractions and contractions, most like a bodybuilder. So it starts to thicken. In certain people, it is so thick— we have criteria to find these patients and direct them to a procedure called thermoplasty. What is it? You're familiar with the bronchoscopy. It is a fiber-optic camera with a light source in the end that I snake through the mouth, inside the voice box, inside the trachea, windpipe, all the way to the lungs. I go to the right lung and I go all the way to the end and I start turning on every 5 millimeters for about 3 to 5 seconds this device. It literally fries the smooth muscle and thins it out. It's very tedious. I have to do each lung at it separately. They have to come back the next week for the opposite lung, and I go 5 millimeters by 5 mil each and every segment, all that tree of lung on the right and on the left. Guess what? It literally is a miracle for these people. They no longer go to the hospital 10, 15 times a year. They no longer have to be on steroids because that's all they had, because now you've opened up their airways mechanically. That is what a bronchiothermoplasty is. Let's talk about biologics. Many of you are confused because there are many names. Who do we prescribe them to? Well, how do I approach my patients? How I do it, I call it. How I do it. Well, you have to confirm the asthma diagnosis. You have to confirm that these patients that are still having uncontrolled asthma are adherent. You have to confirm that they are using the right inhaler technique. You have to confirm that you've dialed up the dose all the way up. There's nothing more to go. To confirm that you gave them the 3 inhalers—ICS, LABA, and LAMA. You have to phenotype and stratify them. What type? Do they have allergies? Do they have obesity? Do they have this, this, and that? You stratify them by the biomarkers. We talked about them. Now you understand what they are: the blood eosinophil count, the exhaled fraction of nitric oxide, the IgE level. Once you have identified the phenotype, then the endotype, you address the comorbidities, treat the reflux, see if they have any cold. I had to tell people they can't work in that, um, grocery store anymore next to the cold section. Once you have addressed all of this, then you move to the optimizing current therapy, and then you start to look at— if I'm going to start biologic, which one? Well, if you have atopic dermatitis, eosinophilic esophagitis, nasal polyp phenotype, Dupilumab. If you have a strong allergic sensitization with IgE level elevated, Omalizumab. If you have a T2 low or mixed features, Tezepelumab. So here's a question: what is the biologic that that is prescribed for both T2 and non-T2? Tezepelumab. It's an anti-TSLP. Some of you call it TSLIP. I love that. These are the biologics. I don't expect you to know them. I don't expect you to, you know, rememorize them. I just wanted you to be familiar with them. IL-5 is mostly mepolisumab and reslizumab. IL-5 receptor blocker is benralizumab. Dupilumab is IL-4 and IL-3. Tezepelumab is anti-TSLP. And omalizumab is anti-IgE. In special populations such as pregnancy, what do we do? Well, we now know, based on our trials, that the— in pregnancy, asthma can be very dangerous for the mother and for the baby. For the mother, literally a mother can die from an asthma attack. Sadly, we start to see— we still see this in 2025. So if the mother has not been on biologics or the mother has been on maximal therapy, maximum optimization of the comorbidities, and still has uncontrolled asthma with exacerbations and hospitalizations, based on chemistry, what receptors could be that will take us decades to find. And now back to Jane. Well, we know now that Jane has a phenotype and an endotype, right? So Jane unfortunately had all of these symptoms and we could start her perhaps on a biologics because she's already optimized and still uncontrolled. And you're right, maybe anti-IL-5, we can start with it so that it lessens the dysfunction of the epithelial barrier, it lessens the chance of long-term fibrosis, it lessens the mucus plug formation, the airway remodeling, and the immune response beyond just the eosinophil. And that's why it was important to phenotype and endotype her. Lastly, you're going to be happy to apply what you just learned on what we now have just done in the proactive feasibility. Thank you for those that helped the COE respiratory. Now we're starting to send all of these surveys globally. We sent one for asthma. Guess what we found? Well, this is a survey that we sent to globally. So far, so far, 60 have answered. I'm sure we'll have more. I mean, it's the summer at the end. We are recording this on August 21st. So these sites, what they told us is capturing the real-world treatment and management patterns of asthma across these clinical sites. We sent a questionnaire that is beyond the feasibility of whether they have a, you know, locked cabinets and lists of who accesses them and a centrifuge and EKG. We wanted to know those patients. Who are those sites that answer us? 65% of them were pulmonologists. 18% were allergists. And then the rest are general practice and other. 55% are private hospital clinic. This is what we want. We want to see what's happening in the communities, not only in the university setting. What about the patients? Only about 30% of them is less than 18 years. The rest were more than 18, and there's a slight preponderance of female more than male. Now, looking at the guidelines, majority use GINA guidelines. We know now what they are. But some use the ATS and ERS guidelines. Pulmonary function tests are done always or most of the time. You can see that some do not have access to PFTs, or they just start people on treatment to see if they can feel better. That is why just because they have a database of patients doesn't mean that they are patients that can be for clinical trials, because they may not have all of the inclusion criteria. They may still need to do them. First-line therapy: ICS. Next-line therapy: ICS/LAVA or triple inhaler if the case is severe to begin with. But guidelines are only the beginning. We need to see what the real world is. What about biologics? Who prescribes them? Specialists. That's why there is a delay in patients getting on biologics, even if they have spirometry and everything else. Primary care waits until they get to the specialist before they have biologics. Do these pulmonologists or specialists switch biologics? And if so, what makes them do that? Like, do you start on dupilumab and move to mepolizumab? Do you start on mepolizumab and move to tezepelumab? Well, they do. Why? Mostly if it's ineffective. Define ineffective the way you wish. There's also a delay of at least 4 weeks, if not more, to get on biologics, mostly because of prior authorization. I think it makes sense— you wait until it's covered by your insurance, especially that biologics are very expensive. Most people cited cost or insurance denials as the barriers to being on biologics. What is the motivation? Lack of efficacy, but also patient preference. Maybe it is because it's every 2 weeks rather than every 6 weeks. Maybe it's because of the side effect. What makes patients stop biologics? They stop the medication or biologics because they feel well. Wow! Let me take you back to that GINA guideline. Escalation therapy. What is the one thing I didn't say? I told you about escalation therapy. I didn't tell you about who do we de-escalate once they feel better. And what's feel better? Does it feel better means that their lungs are better? Do we have any studies that show that feel better and lungs are better, you de-escalate, those patients are not going to go back to the way they were before? We don't know. That's one area we don't know much about—de-escalation. Patients, when they're not told, and they don't— they're not told objectively, do this test and that's gonna give you whether you should remain on the inhaler or not. If they're not told, they will stop the medication by themselves. Some believe that the medication is not needed. Some forget to take the medication. 40%! 1 in 3 or 1 in 4. Guess what? Those patients are maybe the ones that work two jobs. Maybe they have kids to pick up from school. Maybe they are single parents. Maybe they have elderly parents. One in five can afford the medications. That's one of the major obstacles. So the greatest challenge is not only prescribing the right therapy, the right inhaler, the right inhalation technique, the right everything. It's also ensuring that patients understand the value of it and can access it consistently and are given objective ways to know if it works, if they should stay on it. Kevin will like that one because he's one of the biggest proponents of objective measure of when to de-escalate and when to stay on the medication. I think it makes sense. Let's talk about common more comorbidities. Allergic rhinitis, 40% of asthmatics. Obesity, 30%, and gastric esophageal reflux, 1 in 5. So the challenges in de-escalation is there's no clear process, and it's uncertain how to monitor it. What are the biomarkers that are used in practice? Blood eosinophils, pheno, total serum IgE. We knew this, but not as much as we want to see these 100% of the time. Blood eosinophils is gaining traction, 48%. The pheno, 30%. Total IgE, 36%. 53% of the responders said biomarker results made them change the therapy of choice. It's very, very important. So you can see that there is education on behalf of the physician, but there's also education on behalf of the research staff and the patients themselves in the community. So how do we summarize what we talked about today? Well, asthma is endotype and phenotype. Biomarkers are important. Interleukins are beyond just eosinophils. They can actually cause major long-term damage that is irreversible. Small airway disease, mucus plug-in are all endpoints we have to start looking into beyond what we have. Guidelines are widely used, but local context still matters. The clinical practice shapes the therapy of choice beyond the guidelines. Insurance and cost barriers persist, especially for biologics. Patient health beliefs—whether it matters, whether it actually beneficial—and life factors impact adherence. That's why we don't call call it compliance anymore. Comorbidities are common, but they need to look at a holistic care. Did we look at the obstructive sleep apnea? Did we look at the reflux? Did we look at the thermoplasty? And then biomarkers, they offer promise, but their use remains variable. So call to action: education, education. And every time you see me talk to sponsors about patient recruitment, I I tell them, if you can get into the education space and create a landing page with a QR code that people can share amongst each other with your name at the bottom, they can click on it and they can come to you. You will become a leader in this field and you will become trusted because you're educating the patients on what matters to them. And with that, thank you very much. I'm going to ask you to send me any questions that you have on email or on Teams, and I look forward to seeing you on our next project together. And thank you for lending me your ear during this period of time today.