Moderate to Severe Asthma Podcast

Novel Therapies in Severe Asthma Treatment: Precision Medicine, Biomarkers, and New Biologics

Michael Wechsler, MD; Praveen Akuthota, MD


September 07, 2022

This transcript has been edited for clarity.

Michael Wechsler, MD: Hello. I'm Dr Mike Wechsler and welcome to Medscape's InDiscussion series on moderate to severe asthma. This is episode three of the first season, and today we'll be discussing advances in severe asthma treatment. First, let me introduce to you my guest, Dr Praveen Akuthota, who is professor of clinical medicine at the University of California in San Diego where he's a pulmonologist who specializes in asthma and eosinophilic respiratory diseases. Welcome to InDiscussion, Praveen.

Praveen Akuthota, MD: Thanks, Mike, for having me today. It's really a pleasure to be here.

Wechsler: Praveen, I'd like to start off with a couple of icebreaker questions. What can you share with listeners that not many people know about you?

Akuthota: Many people may not know that you and I once rode bikes around the city of Gothenburg, Sweden, where you tried several times to get me hit by traffic. That might be a surprise to some people. That was a fun time and a good conference on eosinophilic diseases.

Wechsler: And we've also shared many other experiences at ball games in San Diego and elsewhere. It's always great to have you. Tell me, Praveen, I've known you for about 20 plus years now. What is it about pulmonary and critical care that first drew you in?

Akuthota: It's a great question, Mike. Like a lot of people, first, the excitement of the ICU was one of those things that made me think as a trainee, hey — I might do pulmonary and critical care medicine. But as I learned more about the pulmonary side of things, that really drew me in. Then it was the eosinophilic diseases, and subsequent to that, asthma, which has guided my career. Mentorship from you and others has been key in this journey in eosinophilic diseases and eosinophilic asthma.

Wechsler: Is there something you wish you had known about pulmonary disease or about asthma when you started practicing that you now know?

Akuthota: When I first started off, I didn't realize how interesting pulmonary disease itself was. At first, it was the excitement of the ICU, but the pathophysiology of airways disease and the inflammation in the airways — I had no idea it would draw me in the way it did.

Wechsler: I totally agree. It's such a fascinating field with so many complicated and complex diseases; certainly, asthma is one of them. Severe asthma has been a big challenge. That's why we've been doing these podcasts to educate physicians and clinicians about severe asthma. We've had a few podcasts already. We talked a little bit in the first episode about precision medicine in asthma with Dr Geoff Chupp, and then we talked about novel clinical trials and the PrecISE Network with Dr Mario Castro. That brings us to advances in severe asthma therapy. I think these are exciting times in the management of asthma because we have so many new treatment options just in the last 7 years or so. We have six or so new therapies that have been approved for the management of asthma. Tell me, what are your thoughts about how far we've come in the management of severe asthma in the last several years?

Akuthota: I completely agree, Mike, that things have come a long way. Interestingly, when I came to my current position in San Diego in 2015, it was a good dividing line between the before times and the after times for the management of severe asthma. It's been the development of biologic therapies that I think have had the greatest impact. Obviously, there are other aspects to severe asthma management that have made some headway as well, including the incorporation of as-needed inhaled corticosteroids. But the development and incorporation of biologics into the practice of severe asthma has been influential, I think, beyond what any of us would have ever thought 7 years ago. This includes the development of the antieosinophilic biologics. My background, like yours, is in eosinophilic diseases, as well. This tied my two worlds together. The development of these antieosinophilic biologics, as well as other biologics, has been key.

Wechsler: We've evolved a little bit. We used to have a one-size-fits-all approach in the way we took care of our severe asthma patients. We didn't really have many options. We had inhaled corticosteroids and long-acting beta agonists. In 2003, we had the emergence of the first biologic in the form of omalizumab that targeted IgE. Tell us how you felt about anti-IgE therapy when it first emerged earlier on in your career and what kind of difference it made for you?

Akuthota: I think of allergists as the people who were using anti-IgE therapy readily. You probably agree, Mike, that in pulmonary practice, even though the medication had been around for a long time by the time other biologics developed, we hadn't been incorporating it into our practices quite as much. I think this is for multiple reasons. Many patients didn't respond. We didn't have a good sense of who would be a responder vs a nonresponder. We didn't have the infrastructure for giving the medication. We didn't really understand biomarkers quite as well either. So I can't say that I actually gave that much omalizumab. I maybe referred my patients once in a while to my allergy colleagues. I think it's after the development of mepolizumab and other biologics that we started to think more about omalizumab, which had been there the whole time. In particular, we started to think about how it came into our entire schema of biologics practice.

Wechsler: When I think back, I found that it was quite revolutionary. It began the period of time where we used some form of precision medicine. We started to at least think about allergic asthma as opposed to nonallergic asthma. I think this was pivotal, and I think it paved the way for the emergence of all the biologics we currently have. After 2003, when omalizumab came out, the next therapy approved was bronchial thermoplasty around 2011. We began to use this for some patients with severe asthma. But again, we didn't really use a precision medicine approach. It wasn't until 2015 when we had the first anti–IL-5 drug mepolizumab approved that we began to see how things changed. You moved to San Diego around then. How did anti–IL-5 therapy change the way you practice medicine? How do you use the anti–IL-5 therapies?

Akuthota: I think my practice is a little bit unique in that it's enriched with people who have eosinophilic disease and who have high levels of eosinophils. But how it's changed my practice — and maybe I was more prone to look at biomarkers beforehand because I was thinking about eosinophilia — is that it made me much more prone to look at eosinophilia as a biomarker. And then it's made me be quicker in patients who are not responding to inhaled corticosteroids and multiple other controller medications to try a biologic. I think we were still trying to understand who a responder and a nonresponder might be, even with people who have high eosinophil counts. I think the incorporation of IL-5 biologics or the introduction of IL-5 biologics made myself and others more cognizant of looking at eosinophilic counts as a biomarker and understanding that these patients might respond to these therapies.

Wechsler: It's been a huge boon for patients whose disease is poorly controlled on inhaled corticosteroids and long-acting beta agonists. We needed other therapies. Approximately what proportion of the severe asthma population does have eosinophilia? And what sort of thresholds do you utilize in terms of identifying someone who's having eosinophilia? Do you ever check sputum at all, or do you do bronchoscopy, or do you just look purely in the blood?

Akuthota: I'll tackle the last part of your question first. I look purely in the blood just from a convenient, pragmatic perspective. There are others who rightfully advocate for the use of sputum eosinophilia, which I think is a little more precise biomarker than blood eosinophilia. There's some infrastructure and resourcing that's necessary to do sputum eosinophilia in practice. I am curious about whether you look at sputum in your practice.

Wechsler: We here at National Jewish do check sputum eosinophilia. We also do a lot of bronchoscopies in our severe asthma patients to try to figure out what else could be going on or what other comorbidities could be going on. We certainly look at the blood in everybody, but in a subset of patients, we look at sputum and/or perform bronchoalveolar lavage.

Akuthota: I think that's completely reasonable. My practice, just from a pragmatic perspective, looks at blood. Back to the original question about what percentage of people seem to have elevated blood eosinophil levels — I think everybody's got a little different perspective depending on what their practice is. We have some guidance from data about what the proportion of people with so-called type 2 biomarkers and non–type 2 biomarkers might be, and about three quarters or more might have some type 2 biomarker elevation. There are data from the International Severe Asthma Registry that also tell us about overlap within type 2 biomarkers, including blood eosinophil count, IgE level, and exhaled nitric oxide. To answer your second question, I would define eosinophilia as an eosinophil count above 300, but it is actually reasonable, and particularly given the dupilumab data and the dupilumab prescribing information, to use a 150 cells/uL cutoff. If you use a 300 cells/uL cutoff and incorporate all the data sources in aggregate, I would say my best guesstimate of the number of patients who have a high eosinophil count would be about 60% of people with severe asthma, and maybe 50% have an eosinophil count of 300 cells/uL or greater. I am curious what your estimate is on this.

Wechsler: It's somewhere between 50% and 60% or so. I agree with you, I think it's a very useful biomarker that's really helped guide us in thinking about how emergency biologics have occurred over the last several years. In 2015, we had mepolizumab, and it targets IL-5; in 2016, we had reslizumab and IV agents that also target IL-5. And then in 2017, we had the emergence of benralizumab that targets the IL-5 receptor and works by a couple of different mechanisms to deplete eosinophils. How have you utilized these therapies, and what has been your approach to choosing between these different therapies in patients with severe asthma?

Akuthota: Great question. There's a lot in there. These therapies have a lot of overlap in mechanism of action. The differences between them are potentially subtle. A patient that responds to one therapy within the anti–IL-5 group is likely to respond to one of the other ones. The question is, how do you fine tune it and predict who might do a little better on one of the anti–IL-5 receptor biologics vs another? I tend to default to prescribing benralizumab for a couple of reasons. There's a little bit better eosinophilic tissue level depletion with the anti–IL-5 receptor blockade vs the IL-5 circulating cytokine blockade. There's also the dosing considerations. After the first three doses being every 4 weeks, it's every 8 weeks after that, which with self-administration, is convenient for patients. There are definitely certain cases, particularly with reslizumab, where the ability for IV weight-based dosing can be helpful, particularly in patients with a higher body mass index. That might be a compelling reason to give reslizumab vs the other medications in the class, and then mepolizumab because it has an on-label indication for eosinophilic diseases, particularly EGPA (eosinophilic granulomatosis with polyangiitis) and hypereosinophilic syndrome. If I'm a little bit unsure whether what I'm taking care of represents an emerging hypereosinophilic process or EGPA, I would potentially be more prone to giving mepolizumab — maybe even at the approved 300-mg dose rather than the 100-mg dose. But these are all great agents. We're really trying to find the subtle distinctions between the three.

Wechsler: I agree with you. And we've seen with all these therapies that the clinical trial data suggests there's around a 50% reduction in exacerbations. What other outcomes have been improved with these biologics, as well as some of the other biologics that we're going to be discussing?

Akuthota: I have to reiterate the exacerbation piece because I think, particularly with mepolizumab and the initial study for mepolizumab, the DREAM study being designed around an exacerbation endpoint was not just important for the drug itself but a sea change in how we did clinical trials in asthma. That was the first big study and a new phase 3 study that used exacerbations as a clinical endpoint. Exacerbations are key. I will reiterate multiple times that these are a huge mechanism of action. There are other endpoints that read out in these trials as well — sometimes lung function, not always, but we do see how FEV1 signals with the anti–IL-5 biologics and the subsequent biologics. Symptom scores and ACQ (Asthma Control Questionnaire) scores do improve. We look at the quality of life score. There are multiple things we look at when we're treating patients with biologics.

Wechsler: We've talked about anti-IgE. We've talked about anti–IL-5. The next thing that emerged was in 2018 was the anti–IL-4 receptor, anti–IL-13 therapy dupilumab. And with that came the concept of type 2 inflammation. Tell me how you define type 2 inflammation.

Akuthota: We use that term a lot, but there's a lot in there. I think that we think of type 2 inflammation as a monolith. It includes eosinophilic inflammation, which includes other so-called T type 2 — shorthand for Th2 — signals that are downstream of the activation of Th2 lymphocytes. This includes the presence of IL-4, IL-13, and again, elevated eosinophils downstream of IL-5, with other signals including increased exhaled nitric oxide and elevated IgE that are all incorporated into it. I think it's maybe a little bit — lazy is the wrong word — maybe it's just a little bit too simple to say that type 2 inflammation is one thing. There is a lot of subtlety within type 2 inflammation. IgE may be elevated out of proportion to the other biomarkers or vice versa. This implies some underlying mechanism as well, being that there's a lot of distinction subtlety between the type 2 biomarkers. I think this means that patients who have elevated type 2 biomarkers are not all the same. That's why we see in clinical practice that one patient might respond to one biologic vs another. We're still learning how to be a little bit better about being splitters rather than lumpers within type 2 inflammation.

Wechsler: There certainly is a lot of heterogeneity across our asthma population. I think another important concept is that the mechanisms of action and the pathophysiology can be quite dynamic in response to different stimuli. You might be exposed to a virus, and sometimes you might be exposed to an allergen, and other times you might be exposed to smoke or some other irritant. Those may take you down different mechanisms of disease and different pathways at different times. I agree with you. It can be a little bit erroneous to say, oh, well, this person has purely eosinophilic asthma, or this person has purely allergic asthma because it is quite dynamic.

Dupilumab emerged in 2018. It was approved previously in 2017 for atopic dermatitis. Since then, it's also been approved for a couple of other indications, including chronic rhinosinusitis and eosinophilic esophagitis, among others. Dupilumab also has some nice long-term data as well that we published earlier this year. What do you see as the role of dupilumab in the management of severe asthma?

Akuthota: I know other people have their own schema for a hierarchy of biologics, but I think of dupilumab as my go to for patients with comorbidities. A patient not just with severe asthma but who might have allergic rhinosinusitis with or without nasal polyps might be somebody in whom I'm more prone to give dupilumab. I also — and I think we all do this a little bit — handicap somebody as being an IL-5 person vs a dupilumab person based on their balance of type 2 biomarkers. Is this somebody who has a little bit higher IgE out of proportion to their eosinophils? This might be a dupilumab person vs somebody whose eosinophil count may be 500 or 600 cells/uL but their IgE level is a little bit lower. Their level is lower but still elevated, and their exhaled nitric oxide level might also be a little bit lower. So, they might be a dupilumab patient.

Wechsler: Yeah, I agree with you. You could also consider how you'd put anti-IgE in the mix, but I utilize exhaled nitric oxide as a key biomarker to help me determine responsiveness to dupilumab; dupilumab lowers exhaled nitric oxide, which lowers IgE levels. When I try to look at the dominant biomarker, if it's certainly the eosinophil count that is much higher than the other biomarkers out of proportion where they ought to be, I consider each specific therapy and each indication accordingly. So we have anti-IgE and we've got the anti–IL-5 that we've discussed. We talked about dupilumab and anti–IL-13. In December of this past year, in 2021, we saw the approval by the FDA of a novel therapy that blocks TSLP, or thymic stromal lymphopoietin — a drug called tezepelumab. Tell us your thoughts on tezepelumab.

Akuthota: I'm excited about tezepelumab. It's still in the early days. I'm excited from a mechanistic perspective because this is something a little bit new and different. This is our first biologic or monoclonal antibody against a so-called alarmin, which is a molecule that's directly produced by epithelial cells in response to injury or stimulation by inhaled irritants or allergens. This may lead the way to other alarmin medications in the future. Anti-TSLP does have decent data, and it's a pivotal phase 3 trial for patients who don't have elevated type 2 biomarkers, though it does seem to work even better in patients with a higher type 2 biomarker. Whether this ends up in the real world, in the wild, being a good medication for patients who don't meet biomarker profiles for the other biologics, or fitting in with patients who already have elevated type 2 biomarkers — think it's still early days, and we're learning exactly where tezepelumab will slot in. I'm excited to have this alternative mechanism of action that will help us understand asthma biology better and help a larger number of patients.

Wechsler: It's the first biologic that's shown efficacy in patients with eosinophilic counts less than 150 cells/mL I find that exciting. And even in patients who've got combinations of low type 2 biomarkers, low exhaled nitric oxide, low eosinophils, and nonallergic status, it seems to be effective in them as well. Do you use an upstream approach and go with tezepelumab in your patients who have severe asthma, or do you tend to go more downstream and target specific biomarkers? What's your approach?

Akuthota: I'll tell you what my approach is today, but that might not be the case a year from now or 2 years from now as we get more data about tezepelumab, in particular, in the real world. My approach tends to be downstream because I think we're still in early days with tezepelumab. I hope we may learn that upstream approaches have actual disease-modifying effects, and that this conversation we're having now — and that you may talk about in future podcasts — about the concept of remission in asthma may dictate whether we take more of an upstream vs downstream disease approach in asthma. But right now, I'm still a downstream person.

Wechsler: Interesting. We've talked about all these new biologic therapies that have been approved. There's been a lot of studies recently about other therapies, including therapies that target another upstream alarmin, IL-33, and a drug called itepekimab that we published in 2021. There have been data on dexpramipexole. There have been studies looking at other novel targets, including the prostaglandin D2 receptor and CRTH2 antagonists. Where do you see some of these novel therapies potentially fitting in? And what's the future of management of severe asthma?

Akuthota: I see still a lot of confusion in the future; with something like anti–IL-33, we'll have to decide how it fits in with anti-TSLP. Is that drug going to be good for type 2–high vs type 2–low patients? And then there is a drug like dexpramipexole that has an oral option rather than an injectable option, which obviously has appeal to patients. I see the landscape possibly becoming a little bit more confusing before we start to consolidate knowledge and understand what the right therapy is for the right patient. I know you talked to Dr Castro in the last episode about the PrecISE network and the kinds of approaches and biomarker-driven trials that might try to refine biomarkers and other novel things like genomic studies. I think studies like that, which try to be better at predicting which biologic matches which patient, are the future. We also need to do a little bit better in the non–type 2 space. Who's been left behind? We have a lot of good type 2 biologics. We have a lot of ongoing innovation in that space, as well. But for the patients who don't have these elevated type 2 biomarkers who we're still convinced do indeed have severe asthma, what are our next steps for them? What more can we do?

Wechsler: Have you utilized combinations of biologics in any of your patients?

Akuthota: Here and there. It's hard, right? Because there's a third-party payer aspect to this. I have had a few patients on combination biologics with some success. I think you and I have talked about this offline in the past, and you've had a little bit of success as well. If we had the opportunity to use combination biologics from a third-party payer perspective, I think we would learn that there are definitely a subset of patients out there who would benefit from combinations.

Wechsler: I think one of the challenges is the cost of these therapies, and I think we're going to need to figure out as a society what to do about the cost and how to bring down costs for our patients and for payers themselves. I'll just say one other point that I'm excited about. I'm excited about different dosing schemes and the potential for longer-acting biologics. I know there's a drug now in trials, a longer acting type of therapy called depemokimab, which is administered every 6 months or so. I think there's a lot of excitement on the horizon. We've made so many advances in the last decade or so, both in terms of developing new therapies as well as our understanding of asthma. I find this to be a really exciting time. I'd like to wrap things up, Praveen; thank you so much for participating today. I'd like to remind our audience that we've had national expert Praveen Akuthota discussing with us novel therapies for severe asthma. We've talked about the importance of precision approaches. We've talked about utility of biomarkers. I think we've learned so much about how different patients respond to different therapies. Thank you so much, Praveen, for joining us. It's been great having you. Any closing thoughts before we wrap things up?

Akuthota: First of all, this was a lot of fun. Thanks for having me, Mike. To reiterate your thoughts, this is an exciting time in severe asthma. A lot has happened in the last few years, and a lot is going to happen in the next few years.

Wechsler: All right. Thanks again, Praveen, and thank you all for joining us for episode 3 of this InDiscussion podcast series. We look forward to having you join us for future episodes. We're going to be discussing multidisciplinary approaches to treatment as well as environmental and social determinants of asthma, and we will talk about pediatrics and childhood asthma. Thank you so much again, all of you, for participating. This is Mike Wechsler for InDiscussion. I look forward to seeing you next time.




Bronchial Thermoplasty

Eosinophilic Asthma and Sputum Eosinophilia

Role of T2 Inflammation Biomarkers in Severe Asthma

Cluster Analysis of Inflammatory Biomarker Expression in the International Severe Asthma Registry

Dupilumab Prescribing Information

FDA Approves Cinqair to Treat Severe Asthma


Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)

Hypereosinophilic Syndrome

Anti-IL-5 Therapy in Patients With Severe Eosinophilic Asthma – Clinical Efficacy and Possible Criteria for Treatment Response

Mepolizumab for Severe Eosinophilic Asthma (DREAM): A Multicentre, Double-blind, Placebo-Controlled Trial

Allergic and Environmental Asthma

FDA Approves Maintenance Treatment for Severe Asthma

Tezepelumab in Adults and Adolescents With Severe, Uncontrolled Asthma

Efficacy and Safety of Itepekimab in Patients With Moderate-to-Severe Asthma

The Targeted Eosinophil-Lowering Effects of Dexpramipexole in Clinical Studies

CRTH2 Antagonists in Asthma: Current Perspectives

Precision Interventions for Severe and/or Exacerbation-Prone Asthma Network (PrecISE)

A Study of GSK3511294 (Depemokimab) Compared With Mepolizumab or Benralizumab in Participants With Severe Asthma With an Eosinophilic Phenotype

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