Moderate to Severe Asthma Podcast

Precision Medicine and Clinical Trials for Moderate to Severe Asthma: The Past, The Present, and The Future

Michael Wechsler, MD; Mario Castro, MD, MPH


August 04, 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 2 of the first season, and today we'll be discussing precision medicine, the PrecISE network, and clinical trials. First, let me introduce my guest, Dr Mario Castro. Dr Castro is the L.E. Phillips and Leonora Carr Phillips, professor of Pulmonary Critical Care and Sleep Medicine in the Division of Pulmonary Critical Care and Sleep at the University of Kansas School of Medicine, where he's also the division chief. Welcome to InDiscussion.

Mario Castro, MD, MPH: Thanks, Michael.

Wechsler: Great to have you here today. You have been doing pulmonary critical care now for many years. What is it about the specialty that first drew you in?

Castro: Well, I love going to my job every day and doing something different. Pulmonary critical care and sleep medicine really offers that to you. In my clinic this morning I saw a variety of patients from general pulmonary to our severe asthma patients and COPD patients. Then, this weekend I'll be on call and in the ICU. So, it'll be looking at one end of the spectrum of our specialty to the other end of the spectrum. And that's really exciting, I think.

Wechsler: I think it's one of the fields that gives a lot of opportunities to get a lot of variety and take care of a lot of sick patients to help a lot of people. Is there one thing that you wish you'd known about the specialty when you started practicing?

Castro: I wish I was smarter back then, but…

Wechsler: You could still rely on your looks, Mario.

Castro: What amazes me is where we have really evolved in our field just looking back over the last 20 to 30 years. Certainly asthma treatment has been revolutionized with the addition of biologic therapy. That's really taking us to that next stage. But there's a lot of areas where we have a lot of room to work. If I was starting out, lung cancer would be my biggest hurdle right now because we haven't really made a lot of progress until just recently with immunotherapy and lung cancer. I always take that biggest challenge and say, hey, this is what I want to take on. That would be the only thing I would look in retrospect and say.

Wechsler: I think I think there's been a lot of excitement in pulmonary medicine, in particular with the new drugs for asthma, cystic fibrosis, pulmonary hypertension, and others. But there are still a lot of unmet needs. In asthma, what do you consider to be some of the biggest unmet needs?

Castro: Despite us having great medications, estimates are that anywhere from 40% to 60% of patients are uncontrolled and not achieving that optimal control. I think there are a variety of reasons for that. Some that we're going to talk about are the medications that they're using are not working for them. But also there's this other side of the coin, which is patients are nonadherent sometimes, and non-adherence is due to a variety of different factors. Some of it could be, not just that the medications don't work for them, but they're just too expensive, they're too cumbersome, or they have side effects. And so there are a lot of patients where we have what we refer to as the implementation gap. We know what works for them, but yet they're not using it or physicians are not using that in their practice. And so that's definitely an unmet need. How do we better cross that gap so that providers are using the latest treatments in terms of asthma? And at the same time, patients are getting the optimal therapy that works for them.

Wechsler: I think that's one of the biggest challenges. I saw someone yesterday also who was a perfect candidate for a biologic, but it turned out she had $1,000 a month copayment and couldn't afford it. I think that we're getting to where we want to be. And one of the big concepts now is precision medicine. How do you define precision medicine for asthma specifically, and where do you see that going?

Castro: I think precision medicine is getting the right drug to the right patient. And that's really just my simplified way of looking at it. We know asthma is a very heterogeneous disease. Wendy Moore and I wrote an editorial about the many buckets of asthma and that when we say asthma, we can really be talking about over a dozen different types of asthma. So precision medicine is really narrowing down what that type of asthma is. Often, we refer to that as understanding the phenotype of that asthma, those characteristics that are inclusive of that particular subset of asthma. And then by understanding what that phenotype is, then if we have the right understanding of the what's driving it, that's what I refer to as the endotype or the pathobiology that leads to those clinical characteristics. Ultimately, we hope that those are treatable traits that allow us then to specifically find a therapy that works for that particular asthma patient. And so that's what I refer to as a precision medicine approach in asthma.

Wechsler: Where do we stand now in terms of precision medicine? How are you utilizing the tools we have to implement precision medicine for your patients?

Castro: I think we are getting there, but we're only part of the way there. In terms of identifying those endotypes we use currently in clinic, there are three different biomarkers: circulating blood eosinophils, exhaled nitric oxide, and IgE. These biomarkers help us identify certain features of our patients, but they're not necessarily specific. I categorize all 3 of these by biomarkers as identifying T2 type of inflammation that is driving that patient's disease. And I think they are variable in their success. So, for example, the total IgE just helps us identify whether or not that patient is atopic or allergic and doesn't give us any more specific information than that. It's not predictive of a response and it's not predictive of response specifically to anti-IgE therapy. When we look at FENO or exhaled nitric oxide, this helps us identify that patient that has T2 inflammation and in particular in some subset of patients that may be driven by an IL-13 driven mechanism in the airway. And then lastly, the blood eosinophils I consider as a surrogate of what's happening in the airway — what we typically define by sputum eosinophils or by tissue eosinophils. When we look at studies that have been done like the BOBCAT study where we looked at correlation in the same patient, these correlations are in the 0.6 to 0.7 range, which I think helps us define why sometimes we think we're doing the right thing because this patient has a blood eosinophil of 350 or 400 cells/μL. We put them on an anti-eosinophil drug and lo and behold, they don't respond to it. And then we scratch our heads, and we figure out maybe that wasn't really an accurate reflector of what was happening in the airways itself.

Wechsler: How much does that reflect the dynamic nature of some of these biomarkers and/or how does it reflect some of the stimuli that can result in elevations in these biomarkers? Because sometimes you can have an allergic predisposition or sometimes you can have a viral that's instigating problems. Sometimes you can have pollution that's causing problems. And so that must cause differential effects across the board.

Castro: Yes. I think that's part of the imperfection. When you think about endocrinologists and how they manage diabetes — glycosylated hemoglobin averages what's happened over the last 90 days. At least that's how I think about it as a pulmonologist, right? When we use our biomarkers, it's really much more reflective of what's happening in that snapshot. It really doesn't give us an accurate assessment of what's been happening over the last several months. So you're right. If somebody has been dancing through the ragweed field and they're highly ragweed allergic when they come in that day, they may have elevation in their FeNO or their eosinophils, but that may not be reflective of how they truly are on a day-by-day basis. I think ultimately, we need to get there in terms of biomarkers, but we're not quite there with the ones that we have.

Wechsler: Where are we going with biomarkers in the future? Are you involved in any work looking at future biomarkers? I know that there are some that have been implicated in the past: periostin, dipeptidyl peptidase 4 (DPP-4), urinary bromotyrosine. Do any of those fit in or do you see any other useful biomarkers that may be emerging in asthma?

Castro: I think all those that you mentioned are certainly candidates. We are investigating in the PrecISE trial a couple of new biomarkers. In one subset of patients, we're looking for plasma, IL-6 levels and in other patients we're looking at their genotype. So there are possibilities of additional biomarkers that we can look at in regards to helping us to identify patients.

Wechsler: You brought up the PrecISE Network. You and I are both involved in that as investigators. PrecISE, for those who don't know, stands for precision interventions for severe or exacerbating asthma. It's a network that's sponsored by the National Institutes of Health and has 10 main sites with 30 sites overall. Mario, why don't you tell us a little bit about the PrecISE network.

Castro: As you mentioned, it's National Institutes of Health. Specifically, the National Heart, Lung, and Blood Institute (NHLBI) has funded the study to really understand the heterogeneous population of patients with severe asthma. This study includes both adults and adolescents. So we are studying patients 12 and above. Our overall goals are really to help us to better identify the types of severe asthma as we were just talking about. There are endotypes that we just don't understand well yet and how do we identify them? And then the second overall goal is to identify new treatments for these variety of patients with severe asthma.

Wechsler: That's really exciting. There are sites all across the country from far south, from Florida to the far west in California to far east, including New York and Boston. And then the middle of the country, Wisconsin and you in Kansas and me in Denver. We have sites all across the country. One of the exciting things about this interesting study is that it uses an adaptive study design. What can you tell me and our listeners about adaptive study designs?

Castro: Adaptive trial designs have been implemented in the past with cancer and other disease states. This is one of the first times it's been implemented in the respiratory field, at least, in this big of a trial. The unique thing about adaptive trial designs is that it allows you to increase the efficiency of the trial over the traditional parallel arm study. So, if we're trying to test a new inhaled steroid, you usually compare it to a placebo or if you're doing a comparative effectiveness trial, we may compare it to some other approved treatment. And you often study those patients to look at their exacerbations over an entire year. That's pretty inefficient because you have to enroll those patients and follow them for a year and maybe several years before we get an answer. In the adaptive trial design, you actually then can choose a particular biomarker. And so you can adapt based on the biomarker. Maybe you've set up cut off, and you can find out after studying the first 40 or 50 patients that cut off is not right. Instead of waiting till 500 patients to change that and do a new trial, you can actually adjust the trial, and so that's the adaptive nature of that. It's also true for the interventions themselves. The adaptive trial design allows us to identify when things aren't working early in the trial and to find them as potentially futile. We have futility rules that we utilize, but it also then allows you to enter new treatments. Say that Dr Wechsler discovers the latest and greatest new drug for severe asthma, and we want to introduce that into PrecISE. We can do that in this adaptive trial design because of the nature and how it's set up.

Wechsler: What are the drugs and strategies that are being evaluated in the PrecISE network?

Castro: There are currently five therapies that we are looking at in PrecISE. I consider each of these therapies in that phase 2a of a clinical trial FDA categorization because these are really not proven yet whether or not they truly work in our patients with severe asthma. Each one of them has some preliminary data, but they're not yet there. We have to keep that in mind as we talk about PrecISE, because it's not going to find the final answer for any of these therapies, but it's going to lead us to that next step as a phase 2a would. One of the therapies that we're looking for T2-low disease is imatinib, which is a c-Kit inhibitor. And we understand that based on an earlier study led by Katherine Cahill, that this might work in patients that have mast cell driven disease because of this effect on the c-Kit inhibitor. The second intervention that we are studying has to do with a group of patients that I really have struggled with over the years, which are my obese patients with metabolic dysfunction. We proposed to use plasma IL-6 as the biomarker, and we're studying an anti-IL-6 called clazakizumab. So clazakizumab certainly has a wealth of data outside of the pulmonary field, but this will be its first application within this targeted population.

Wechsler: Are there any safety concerns with targeting IL-6?

Castro: I think we are screening for that in terms of patients. We are always concerned about any patient that has underlying immune dysfunction or has a predisposition to TB or mycobacterial disease or other things like that. There are screening tests that are in place in order for us to catch that before they get into that part of the trial.

Wechsler: You mentioned imatinib, clazakizumab. What are the other three therapies that are being studied?

Castro: One other one that we're studying that's relatively new is cavosonstat and this is a S-nitrosoglutathione reductase (GSNO) inhibitor. And we're actually using a genotype to identify those patients that have high GSNO activity. So by selecting by genotype, using that as your biomarker, you may find that subset of patients that respond very well to cavosonstat. The other one that we are studying is a bacterial extract called Broncho-Vaxom. And believe it or not, this bacteria extract has been around for decades in Europe as an over-the-counter therapy, and it's been through the FDA process and purified. Now we're studying it for the first time in severe asthma and we're using this potentially as a modifier in T2 asthma, identified by high blood eosinophils. The last one, which is exciting because my patients always ask me about dietary approaches to asthma, is actually by enriching your medium chain triglycerides (MCT). This nutritional supplement is an MCT supplement that will allow you to enrich somebody's diet in that regard. We're targeting patients that have high arginine type of metabolic asthma and we're using FeNO actually greater than 15 parts per billion and monitoring their blood ketones as a way to monitor this therapy. So, all five of these are pretty exciting, Mike. If we can really pull off this PrecISE trial, I think it's going to give us some exciting new options down the road.

Wechsler: I'm really excited about the prospects of all these therapies and really hope that a few of them at least make it through and show some degree of efficacy. Because as you mentioned before, there's a huge amount of unmet need in patients with severe asthma and particularly those patients who've got non-type 2 asthma and patients with obesity associated asthma. We're really searching for answers. Those I find, are the most challenging kinds of patients for us. The study is enrolling now. And how is the study going?

Castro: Well, we have all lived through this COVID pandemic and so PrecISE took a big hit. It's really just getting back on its heels across all those 30 sites you mentioned and starting to enroll patients. We are still early. We have less than 200 patients enrolled. We're aiming for 600 patients. So, we're less than a third of the way there. We really do need everybody's contribution in order to make this successful.

Wechsler: I often get asked by many of my patients, why should I participate in a clinical trial? Aren't there good therapies out there? Why should I do it? So tell me why. What do you tell your patients?

Castro: Ultimately, it's their decision. And I tell them that upfront and that I respect their decision and I'm trying not to influence them in that regard, but I am trying to open their eyes that participating in a clinical trial gives us additional tools that I don't have in the clinic. I can do a sputum eosinophil in my research study, but I can't do it in my clinic. So we have different ways to evaluate our patients as part of the clinical trial. All the patients would have access to that information. The second thing I tell them is that one thing that I have always learned through the years that my coordinators do is, they help patients understand their asthma much better. If you're seeing somebody, not day in and day out, but if you're seeing them pretty often over a year's period of time, you get to know a lot about that patient and you get to teach them a lot about why their medications are important, what's special about their asthma and how can they better take care of themselves. I think that ultimately is why a lot of my patients that participate in clinical trials come back. They enjoy that part and believe that they have much better understanding of what's happening to their bodies. The third thing I say is that these are treatments that are not available. My doctor in Garden City, Kansas, can't go prescribe this particular medication, but you would have potentially access to this medication as part of a clinical trial such as PrecISE. And there's always that chance you get placebo. But in this trial, there is that enriched kind of randomization schedule. So the risk of that placebo is relatively low in terms of the chance of you getting that.

Wechsler: I agree. Those are some of the reasons I give to my patients. Plus usually we cover the costs of some of the controller therapies if they're on inhaled steroids, long-activating agonists. Oftentimes there's an honorarium so patients can get paid. And I think actually a lot of our patients want to help society and really try to advance the science. And I think that is a carrot that draws many of them to do this. And also, I think the regular visits also some patients find reassuring when they come and see us on a monthly basis. They want to know how their asthma is doing. So you've been involved in other networks, in the AsthmaNet, in the SARP network, the Severe Asthma Research Program. Can you give us just some of the highlights of what's emerged from some of those networks?

Castro: Sure. The SARP sponsored again by the National Institute of Health NHLBI, over the last 20 years, has really given us the tools that we use right now in the clinic in terms of helping us identify that T2 subset of patients. And understanding that that's often driving a significant proportion of our patients in terms of their disease status. But what SARP is doing now, which is pretty exciting, is studying the other half of the point, the non-T2 population. And as I mentioned earlier, with that metabolic dysfunction, that's definitely a target for us in this next cycle of SARP and helping us understand what the right biomarkers are, and what's driving that disease process in that regard. The other network that we're part of is sponsored through the American Lung Association. This is the Airways Clinical Research Center. And in that network, we just launched one of the largest lung health studies. It's called the Lung Health Cohort. And we're studying 4000 millennials that are 25 to 35 years of age. And basically, what we're trying to do is, everybody gets a quantitative CT, detailed characterization, and we track what they're exposed to in terms of vaping, environmental exposures. We're trying to establish basically the Framingham Study of the lung. And so the Lung Health Cohort, is really an exciting study that people can participate in and really will, I think, set the stage for the future.

Wechsler: I think that's really exciting. I think we're going to learn a lot from that study, from the SARP studies and certainly from the PrecISE network. This has been a great discussion and thank you so much for participating today. We've had national expert, Mario Castro, today discussing with us clinical trials on asthma, the past, the present and the future. And I'm really excited about the prospects for our patients with asthma. This is an important topic. There's still a lot of unmet needs. Thank you so much for joining us, Mario, and thank you to our listeners as well for joining us. We look forward to episode 3. Mario, any closing comments?

Castro: No, I'd just like to thank Medscape for getting this out there and this information. And for those that are listening, recruit more people in the pulmonary critical care. It's an exciting time.

Wechsler: Great points. Thank you so much. Again, thank you to our listeners, this is Mike Wechsler for InDiscussion. We'll catch you next time.


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


The Many 'Buckets' of Severe Asthma: Moving Toward Personalized Managements

What is Fractional Exhaled Nitric Oxide (FeNO) in Pulmonary Function Testing?

Periostin is a Systemic Biomarker of Eosinophilic Airway Inflammation in Asthmatic Patients

Asthma Workup Approach Considerations

PrecISE: Precision Medicine in Severe Asthma: An Adaptive Platform Trial With Biomarker Ascertainment

KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma

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

Designing Clinical Trials to Address the Needs Of Childhood And Adult Asthma: The National Heart, Lung, and Blood Institute's AsthmaNet

Airways Clinical Research Centers

Lung Health Cohort Study: Making History

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