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Michael Wechsler, MD: Hello. I'm Dr Mike Wechsler. Welcome to Medscape's InDiscussion series on moderate to severe asthma. Today we'll be discussing the challenges of moderate to severe asthma, and we'll be reviewing unmet needs and future therapies in asthma with Dr Ian Pavord.
Ian is professor of respiratory medicine at the University of Oxford and honorary consultant physician at the Oxford University Hospitals. Welcome everybody to InDiscussion. Ian, it's great to have you today. What I know about you is a little different from what everyone else knows about you. Most people recognize you as a respiratory physician who's been leading many of the clinical trials in severe asthma for the past few decades. What I know about you is that you are an outstanding golfer. In fact, you are probably the best golfer I've ever played with. The last time we played, just a couple of weeks ago, you actually got an eagle on the 18th hole, which was incredible. Tell us something that other listeners may not know about you, other than your respiratory and golfing prowess.
Ian D. Pavord, DM: I'm a Welshman. Not many people know that. But it's very important in the United Kingdom. And I'm the first professor of respiratory medicine at the University of Oxford, which is a 1000-year-old institute. Now you have two things. But I want to talk about the golf a bit more. I can talk you through the eagle in fine detail if you'd like.
Wechsler: We're going to have to have a whole other podcast about your golfing prowess. Maybe at that time you can also try to help me with my golf swing. Tell us, what was it about respiratory medicine and asthma that first drew you into this specialty?
Pavord: I had asthma as a child, and my mother had it, and her mother died of asthma. At the time, you shrug those things off and get on with it, but I remember whenever I went to friends' houses or was in contact with pets, I couldn't breathe. That would last for a few days, and I just got used to it. This was the way my life was until I started an inhaled steroid as a 10 year old. I was probably one of the first people to be put on it. Suddenly, my life was normal, and it was a revelation. I was very interested in asthma from that point. The second factor was that I really liked pulmonologists. I thought they were the nicest doctors I came across when I was training. What about you, Mike?
Wechsler: I initially was fascinated by critical care medicine. I found that it touched on a lot of different specialties and there were many challenges. In the United States, when you do critical care medicine, one option is to do it in combination with respiratory medicine because of the importance of the lungs and use of ventilators in those kinds of patients. Once I decided to go into respiratory medicine, I had a tremendous group of mentors, including Jeff Drazen, Elliot Israel, and Scott Weiss. They are the ones who really inspired me to move into asthma research where there was a significant unmet need. I knew of this need from kids I grew up with as well, who had issues similar to you — carrying around an inhaler and having shortness of breath.
We've really come a long way since we were both kids. The practice of asthma management has changed so much over the past several decades. When we were younger, there weren't a lot of options. You had bronchodilators and then inhaled corticosteroids, and maybe theophylline was around, as well. Tell us a little bit about how asthma therapy has evolved in the past 30-40 years.
Pavord: I've been treating asthma patients for nearly that long and particularly those with severe asthma. Our job was tough to do because although we could help some of our patients with oral corticosteroids, for example, we had this really uneasy feeling that we were doing harm as well as good. We could get into a situation where we wondered whether the treatment was worse than the condition, and patients developed more and more problems. Some of the problems were linked to treatment, but others were linked to incompletely controlled asthma. There is a massive unmet need for better treatments, particularly in these patients with more severe asthma. That's where the big advances have been. We're both very lucky to have been in the middle of this. It's been a very, very exciting past 10 years.
Wechsler: In the past 25 years, we've evolved from just having inhaled steroids and beta-agonists to the development of leukotriene modifiers, which have had a modest impact in terms of improving lung function by reducing inflammation. And then in 2003, just 20 years ago now, there was development of the first monoclonal antibody targeting immunoglobulin E with omalizumab, and that was a big paradigm shift. How have things changed since that time for you, in the past 20 years, as we've had other biologic therapies evolve?
Pavord: The key thing is the recognition that there are phenotypes of asthma and particularly the identification of type 2 airway inflammation as a key driver of many of the clinical problems our patients with severe and less severe asthma have. This has become an identifiable process with the discovery of simple, clinically accessible biomarkers, and these biomarkers are incredibly predictive.
Wechsler: It's been a huge paradigm shift. Even 10 years ago, people were not measuring eosinophils or nitric oxide routinely, and now it's part of routine practice because we really want to know what type of asthma our patients have. Asthma is a very heterogeneous disease, and one of the biggest advances has been our appreciation of the heterogeneity and complexity of asthma and all the different cells involved. It isn't just eosinophils, it isn't just neutrophils, and it isn't just mast cells. The epithelium is involved, and then on top of that, we have identified novel cytokines — not just interleukin (IL)-4, 5, and 13 — but the alarmin cytokines thymic stromal lymphopoietin (TSLP), IL-33, and others. That's been huge for us and led to several novel therapies that have changed the way we see and manage these patients.
Pavord: Absolutely, and these drugs are highly targeted. They have an enviable safety record, and we can largely predict who's going to respond using simple biomarker measurements in clinics. When you can identify a process that is linked to a good treatment response, you're in a really good position. These biologic drugs have done incredibly well. They've changed the landscape. Severe asthma is a very different beast than what it was 10 years ago. And they've got us thinking about where we are going with these drugs. We have many patients who have high biomarkers but have not yet progressed to severe asthma. Should we be treating these patients in order to prevent downstream problems? These are really exciting concepts. There are new cytokine targets. You've been very involved in some of the new upstream targets such as anti-TSLP and anti–IL-33. Where do you think these fit? We've got, in a way, an embarrassment of riches now.
Wechsler: My feeling is that we do and we don't. In the past 8 years here in the US, in the UK, and globally, there's been approval of three different anti–IL-5 therapies — mepolizumab, reslizumab, and benralizumab. We've had approval of anti–IL-4/IL-13 therapy with dupilumab, and we've had approval of anti TSLP therapy with tezepelumab. What these therapies have been shown to do is reduce exacerbation, reduce steroid dosing, improve symptoms, improved quality of life, and improve lung function. I'm concerned about what they haven't done, which is that they haven't eliminated asthma exacerbations. They haven't eliminated the use of corticosteroids in majority of patients. They haven't resulted in complete improvement or reversal of lung function in many of our patients. Lately, we've been talking about remission as an outcome, but only somewhere between 15% and 40% of patients can achieve remission with these therapies. What are your perspectives on the unmet needs? You can look at the glass half full or half empty. We're so fortunate from a glass half-full perspective. On the other hand, there are still patients out there who need other therapies. What's your perspective on this?
Pavord: That's an excellent summary of where we are. Why is there is a lot of asthma left in many patients despite treatment with a biologic? What we don't know is whether that asthma reflects damage that was done as a result of unchecked type 2 airway inflammation and other processes. If we got in earlier with these drugs, might we prevent that damage and achieve remission? Are there other targets? Are there other biological processes that we can tease out, modify with specific drugs, and show clinical benefit? For example, the macrolide effect seems to occur independent of type 2 airway inflammation. What's that about? Can we understand why macrolides have a big impact? Can we improve treatments and perhaps nonantimicrobial macrolides? Sometimes in medicine, knowing very clearly what you can't do is just as important as knowing very clearly what you can do. We are getting closer to that, but my guess — and I want your view on this — is that quite a lot of people I see don't achieve a very vaulted clinical state–like remission. The primary reason they don't achieve this is that they are irreparably damaged by their disease, and we've potentially missed an opportunity to achieve remission by getting in a bit earlier. Certainly in the UK, that's my feeling. It may be different with you.
Wechsler: My feeling is that there's probably multiple reasons why patients don't respond to the currently available biologics who we would think might otherwise respond. I don't think we do a good enough job of addressing comorbidities, whether it's severe reflux disease, aspiration, sinusitis postnasal drip, or sleep apnea. That's one perspective and one component of all this.
The other component is that asthma is very dynamic and heterogeneous. While a patient might appear to be eosinophilic, for instance, at one time point, they might have some other environmental stimulus, whether it's an irritant or an allergen, which might produce a different mechanism of disease. We're good at blocking a dominant pathway, but sometimes we need to block multiple pathways. I liked what you said about maybe treating earlier in the disease. What do you see as some of the barriers to doing that, though?
Pavord: The major barrier is that people are not measuring these key biomarkers. We tend to focus on measuring damage rather than disease activity, and we need to move that around. The patients we really need to see are people with very active high-risk disease but before the consequences have played out and they have developed all the comorbidities you just outlined. Measuring a patient's biomarkers and finding eosinophilia is significant, and a patient with obstructive airways disease is always a significant finding. It's a very useful finding. It allows you to make predictions. Exhaled nitric oxide is a simple test to do. It takes 5-10 seconds, and you get an immediate result.
Why aren't we doing that? It doesn't require a specialist technician to do this measurement. It can be done in a pharmacy or a primary care center. That's probably where we need to go. It takes a bit of time to get this mindset out there, and guidelines probably need to be a little more ambitious, in my view. But it's an obvious direction for us to go, and it's an exciting opportunity because in airways disease, we haven't been "predictors and preventers." We've been anything but "predictors and preventers." We wait until our patients' lungs are really badly damaged and they've got a lot of other clinical problems, and then we take them seriously. It would be lovely to turn that around before we hang up our stethoscopes and disappear into a retirement full of golf and eagles and other things.
Wechsler: I wholeheartedly agree with you about the underutilization of biomarkers. You and I have had discussions where we've compared not evaluating all the biomarkers to not doing a complete cardiac catheterization. If you don't look at the right coronary, you're going to miss out on potential disease there. It's the same thing by not measuring nitric oxide. You might be missing something. The other barrier that I see is cost. These biologic therapies, while very effective, are quite costly. We're going to have to generate really sufficient data to support their use in patients with disease of lesser severity and earlier on in the disease in order to justify the cost of these therapies in aggregate.
I know there are strict regulations in the UK by the National Institute for Health and Care Excellence (NICE), and I think payers in the US will also restrict with lesser severity. There's one concept of treating earlier in disease, and the other concept might be treating earlier in life. Maybe we need to do studies in that area. There's one study with omalizumab now that's being done. Omalizumab is being given to kids who are 2-3 years old who are at risk for asthma. We need to generate some of these data points, as well.
Pavord: That would be great. Cost is a big issue in the UK. Of course, the rheumatologists had this issue 20 years ago with their biologics, but costs have come down very substantially. I think people have been surprised how successful biologics for type 2 asthma have been when you have a predictive biomarker. It incentivized doctors to go looking for these people, and I think that has been happening. When the drugs are selling well, hopefully costs will go down. And then there are nonbiologic antieosinophil strategies out there that may work and may be less expensive. I'm not as gloomy as you may be about prospects there. I think we'll see costs coming down.
Wechsler: I would love to see that, but we know how society works, and sometimes you have to follow the money trail. You touched on the use of macrolides. I view them as particularly useful where there's a gap, which is in the patients who don't have non–type 2 asthma. Can we talk a little bit about that unmet needs of patients with non-type 2 asthma? What's your current strategy for these patients? And where do you see the non–type 2 asthma field going in the future?
Pavord: The clinical scenario, I think, is either a highly symptomatic patient who has low biomarkers or a patient who's continuing to have exacerbations despite low biomarkers, and sometimes both. If it's a symptom issue, my first thought is, are there comorbidities here? Obesity is the number one comorbidity, and it is much more important, interestingly, in women than men. This is probably because women's lungs for a given height tend to be a bit smaller. Because of this, the restrictive effects of obesity are noticed more. Obesity is a massive cause of symptom-high, type 2–low asthma. There's a real danger in these patients of unnecessary and completely useless escalation of steroid therapy, which can also cause problems. If the problem is an exacerbation problem, my first thought is airway infection.
Older patients with damaged airways are particularly likely to have this issue. Sometimes they respond well to their biologic, but then they develop this problem. They're probably the patients that macrolides are helping. I think the AMAZES study would support that suggestion.
Wechsler: I agree. I think there still is an unmet need. We've utilized bronchial thermoplasty in patients with non–type 2 asthma. We've also seen data that support the use of tezepelumab in patients with noneosinophilic and nonallergic asthma. These are some options we have now, but I view this to be an area of significant unmet need.
Although we think the non–type 2 asthma patients really only represent 20%-30% of patients, there's probably still some other opportunities there. You mentioned obesity, and we know that IL-6 is a marker of systemic inflammation, particularly in obese patients. Targeting anti–IL-6 with anti–IL-6 therapies might be an option.
That's something that we're doing currently in the PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone Asthma) Network. What are some of the other potential targets you're excited about in patients with non–type 2 asthma in which there might be some other opportunities?
Pavord: I think you were involved in Elliot Israel's imatinib study, which was published some years back now in The New England Journal of Medicine. I thought that was an interesting proof of concept study showing an improvement in airway hyperresponsiveness. I think there was a reduction in serum tryptase and more than a suggestion that there may be a mast cell–mediated beneficial effect. I thought that was interesting, and that treatment effect was seen in patients with type 2–low asthma. I'm sure we'll hear more about that drug and related kinase inhibitors that might have a mast cell–specific effect.
Wechsler: Another tyrosine kinase inhibitor that's been studied is masitinib. But there's certainly other therapies that could be appreciated to be effective in non–type 2 disease. I'm excited about the possibility of using JAK (Janus kinase) inhibition in these patients, and there are both oral and inhaled JAK inhibitors. What else are you looking forward to?
Pavord: Don't forget the basics, including optimum bronchodilation, and the addition of a LAMA (long-acting muscarinic antagonist) to a LABA (long-acting beta-2 agonist) can be helpful if airflow obstruction is a treatable trait. The CAPTAIN study I was involved in that looked at the addition of umeclidinium showed that the benefits are really seen across the type 2 asthma spectrum. They're not in any way linked to type 2 inflammation. That's a benefit you get in type 2–low asthma as well as type 2–high asthma in contrast to inhaled steroids or higher dose inhaled steroids, which really won't do anything in type 2–low asthma.
Addressing obesity directly with these glucagon-like peptide-1 agonists is an exciting prospect. They're going to be game changers when they get out there. I think there's a bit of an issue, though, and certainly in the UK. We can't get hold of the drug. There's a capacity issue, and we need to get asthma included as a medical problem linked to obesity, so that we can make a case for addressing the obesity. It's a huge issue in the UK, and we showed that in the RASP (Refractory Asthma Stratification Programme)–UK study. This was a bit like your PrecISE Network — obese females with highly symptomatic type 2–low asthma really have a miserable time. They accumulate lots of treatment, probably a lot of it futile and maybe damaging them. They have a really poor quality of life and very high rates of comorbid depression and anxiety.
Wechsler: There certainly is a need for steroid-sparing agents or safer corticosteroids that perhaps target the glucocorticoid receptor. I'm also excited about longer-acting biologic therapies. We've been involved in discussions about long-acting anti–IL-5 therapies like depemokimab and long acting anti-TSLP therapies. I'm really excited about the future. We need to amplify the things we're doing well and get more people to check biomarkers and assess asthma control. We probably need to give these therapies to patients earlier. We need to have a better understanding of other biologic targets, pathways that are involved, and other biomarkers. Although if we're not utilizing the biomarkers we have now, then I don't know if we'll utilize novel biomarkers in the future, but that's something else to think about. I'm going to give you the last word, Ian. Where are we going in asthma?
Pavord: I was hoping you'd say that. Yes, absolutely, that's where we're at. And in the UK, which is a healthcare system not known for tolerating high costs, there are thousands of women who are on a biologic twice a year to prevent them fracturing their neck of femur or losing height because of osteoporosis. That's an accepted practice. But we don't protect people's lungs in the same way, and maybe we've got an opportunity to do that and move downstream. No one's suggesting we treat mild disease. We're treating very active disease in people who are not yet badly damaged by it, which is a very different thing.
So we're using biomarkers to identify high-risk people, and we're getting in before that biology destroys the patient's lungs and life. That's really where we need to go. We should hang around and try and push this as best we can, Mike.
Wechsler: Absolutely. There's still so much we don't know and so much we think we know that has really prevented us from moving forward. In some ways, I think it was Claude Bernard, the French physiologist from the 19th century, who said, "it's what we think we know that keeps us from learning."
We have to recognize our limitations and keep on learning and understanding what's going on. With that, I want to wrap things up. I want to thank Professor Ian Pavord, our guest today. And thank you to the audience for joining us today. We look forward to future topics. This has been Dr Mike Wechsler for InDiscussion.
Listen to additional seasons of this podcast.
Resources
Type 2 Inflammation in Asthma and Other Airway Diseases
Considering Biomarkers in Asthma Disease Severity
Epithelial Cell Alarmin Cytokines: Frontline Mediators of the Asthma Inflammatory Response
The Immunomodulatory Effects of Macrolides-A Systematic Review of the Underlying Mechanisms
NICE (National Institute for Health and Care Excellence)
Mechanisms of Non–Type 2 Asthma
PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone Asthma) Network
KIT Inhibition by Imatinib in Patients With Severe Refractory Asthma
Optimizing Asthma Management: Role of Long-Acting Muscarinic Antagonists
Claude Bernard, the Founder of Modern Medicine
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Cite this: The Future of Asthma Care: Glass Half Empty or Half Full? - Medscape - Oct 11, 2023.
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