Targeted Pathology and Associated Biomarkers in Asthma

Peter L. Salgo, MD: How do the biologics impact the asthma inflammatory pathway, and what is the targeted pathway for the treatment of asthma in the first place?

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: First of all, you have to talk about what phenotype, and I assume we’re talking about the T2 [type 2]-high, whatever you want to call it.

John J. Oppenheimer, MD: T2-high.

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: The allergic inflammatory pathway, and we’re looking at cytokines like IL-4 [interleukin-4], IL-13. And then there’s the minority, which is the eosinophilic, hypereosinophilic, and that is probably your IL-5 family. Are there others that you can…?

John J. Oppenheimer, MD: Well, then there’s the T2-low, which in severe asthmatics some would argue might represent up to 50%, which is a little bit worrisome.

Peter L. Salgo, MD: OK, now we have biologics. You mentioned all these markers and there’s pathways. Parse this out for me in some way.

Don A. Bukstein, MD: We only have 5 biologics approved for asthma, and they fall into 3 categories. They fall into omalizumab with its [anti-IgE], which was the first biologic. They fall into IL-5 modifiers. We have 2 that work directly on IL-5, one directly on the receptor of IL-5. And then we have an IL-13, IL-4 monoclonal antibody, dupilumab. So we have these 3 categories, and really from a biomarker point of view, we really have 3 biomarkers that we typically do that help us. We have an eosinophil count and an IgE [immunoglobulin E] level, and then of course we have skin testing done early on as we talked about before.

Peter L. Salgo, MD: Do the different biologics require different biomarkers to track them?

John J. Oppenheimer, MD: That’s the million-dollar question.

Don A. Bukstein, MD: That’s the money question.

John J. Oppenheimer, MD: In essence, right now, all of the circles are coalescing. These are all T2-high. So we have the same markers, and the million dollar question is can we really, using your word, can we parse further to really differentiate who might respond to one biologic versus another?

Don A. Bukstein, MD: A good example is FeNO [fractional exhaled nitric oxide], or ENO. Exhaled nitric oxide is a good marker for the omalizumab anti-IgE, and it’s a good marker for the dupilumab, IL-4, IL-13. [It] hasn’t proven to be a good marker for the IL-5s, the eosinophilic. Eosinophils is a pretty good marker for all of them. If you enrich whatever study you’re doing with people with higher eosinophil counts, and of course, children have the highest eosinophilic counts and they tend to do the best on these biologics when you ferret out that group. It gets to be ones overlapping another.

John J. Oppenheimer, MD: And to build upon that, there’s a really interesting study done by Nick Hanania [MD] that looked at omalizumab. So you talk about omalizumab, and for years we were focused on IgE and a perennial positive skin test. And he shows if you enrich the population with an elevated ENO, you get an even better responder analysis.

Don A. Bukstein, MD: And you even get, first we couldn’t see in that patient population, improvement in lung function that was all that great. But when you enrich for eosinophils, you even see improvement in lung function.

Peter L. Salgo, MD: Are the pulmonologists, or the allergists for that matter, out there testing for any of these biomarkers, all of these biomarkers? Is it routine?

Don A. Bukstein, MD: I’m going to tell you, I just reviewed a paper that looked at 300,000 patients. And the fact was, these were pulmonologists and allergists, these were patients that were being evaluated to be put on a biologic. And only 43% of those, whether it was allergists or pulmonologists, was an eosinophil counter.

Peter L. Salgo, MD: Really? But that’s the cheap one.

Don A. Bukstein, MD: That’s the cheap one. So, again, we’re not doing these tests enough.

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: Well, one of the issues with that, and I run into this in clinical practice all the time, these are more severe asthmatics, therefore they’re often on prednisone. And what does that do to eosinophil counts? So you have to go through their chart trying to find a pre-prednisone eosinophil count, plus it drops your IgE.

Don A. Bukstein, MD: Yes, it does change it if they’re actively on oral steroids. My experience is though, the eosinophil count comes back very quickly if they’re eosinophilic type of patients we see, I’m an allergist and a pulmonologist, and so there’s no question it has a little effect on the total IgE level. But it’s not a huge problem.