Identifying the Biomarkers for the Treatment of Severe Asthma - Episode 10
Neal Jain, MD, FAAP, FAAAAI, FACAAI: So let’s move forward and talk about that, because we’ve talked a little bit about mepolizumab, we’ve talked about Xolair, or omalizumab, and we have now 5 products on the market. What are the differences in mechanism of action between these different therapeutics? Are there biomarkers that help us to identify 1 therapeutic as perhaps being more favorable in response based on those biomarkers?
Nicola A. Hanania, MD, MS: We talked about the asthma phenotypes and looking at eosinophilic versus allergic. There’s quite a bit of overlap. Obviously, when you’re using omalizumab you’re really targeting allergic asthma. It’s been tested in only those patients who have peritoneal allergies, documented either by skin tests or RAS testing. And certainly, the studies have shown, at least the real-life studies, that blood eosinophils don’t really play a role in determining response to omalizumab.
Bradley Chipps, MD: I think that’s important because even the French study that just published showed us that even with low eosinophil counts there was a solitary response to omalizumab. I think that was helpful information.
Nicola A. Hanania, MD, MS: On the other hand, the anti—IL-5s: There are 3 of them. Blood eosinophils are an important determinant of response; also, severity of the disease. The higher the exacerbation rate, the higher blood eosinophil, the better response to anti–IL-5 therapy. It doesn’t matter which 1 you’re talking about.
Bradley Chipps, MD: And possibly to the IL-4/IL-13 drug too.
Nicola A. Hanania, MD, MS: So with IL-4/IL-13, it’s interesting. We’ll talk in more details about it. Eosinophils seem to be a good determinant, but exhaled nitric oxide level is also a good predictor of response because it’s targeting type 2—high asthma. So there are certain biomarkers that help us. Having said that, you can see there is quite a bit of overlap. For example, an anti–IL-4 can lower IgE, and it does work in allergic asthma as well as eosinophilic asthma. A subpopulation of allergic asthma responded to anti–IL-5 therapy if they had high blood eosinophils.
I know Brad presented, at this AAAAI [American Academy of Allergy, Asthma & Immunology] meeting, some data from omalizumab showing that it can lower blood eosinophils. The high-blood-eosinophil patients respond as good as low-blood-eosinophil patients in at least the real-world studies.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Right.
Nicola A. Hanania, MD, MS: So there’s quite a bit of overlap. I think the choice of which 1 to use will rest on several other things, including the comfort of the clinician, but the patient also. That’s where shared decision making is important.
Bradley Chipps, MD: And looking at comorbidities too, I think.
Nicola A. Hanania, MD, MS: And comorbidities.
Bradley Chipps, MD: That’s very important, as we had the discussion about whether to attack the IL-5 pathway, the IL-4/IL-13 pathway. If they have nasal polyps and atopic dermatitis, you’re going to tend to mitigate to the IL-4/IL-13 pathway. As for eosinophilic disease with or without nasal polyps, you may decide to attack the IL-5 pathway first.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Right.
Aidan A. Long, MD: You know, something that struck me is that there’s a difference in the population of patients, all type 2 high, who may appear to respond to omalizumab and those who respond to the anti—IL-5 drugs. Omalizumab was initially tested in mild to moderate asthma, allergic asthma. It was also shown to work in severe asthma, in sharp contrast to the anti–IL-5 agents, which, in all-comers asthma, really didn’t do very much.
Nicola A. Hanania, MD, MS: Almost killed it to start out with.
Aidan A. Long, MD: And only when a very specific class of patients was identified, which Nic discussed before, who truly had persistent eosinophilic asthma despite high-dose anti-inflammatory medications, when you look at the patients who were in the studies, they were really remarkable.
Bradley Chipps, MD: Late-onset disease.
Aidan A. Long, MD: Despite those medications, they were having 2 or 3 exacerbations a year and had around 30% to 40% reversibility. So it’s a very distinct class of patients. It’s very different from the omalizumab response in patients that appeared to be across a broad spectrum. And I think perhaps the anti—IL-4/13 may have a different population. Again, it may be broader than the anti–IL-5s. So it’s based on not just the markers but also the phenotype of that patient. The anti–IL-5 patient group in the study was a very interesting subset of asthma.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: I think that that’s an important point. The way I think about IL-5 therapies and these really high eosinophil levels—not necessarily very high, but certainly you see that bigger response in those patients who have more eosinophilia, more exacerbations, and it is important to note that. You know, when I think about eosinophils, I think about them as an amplifier of this immune response that’s sort of already sort of going on, right?
And then coming back to Xolair, I’m curious to hear your thoughts on this PROSPERO trial. You go back to the initial studies in Xolair, the placebo-controlled trials, and there were 2 trials that came out positive. One wasn’t quite so positive in that a severe population of patients were on LABAs [long-acting beta agonists] plus high-dose ICS [inhaled corticosteroids]. But then we see PROSPERO showing that maybe there is an effect. We bring in ideas about adherence, etc. So how do we put all of this together?
Bradley Chipps, MD: I think you have to look at the age of the patient. And I think you have to look at the intensity of the eosinophilic signal, and the peripheral blood compartment, and the airway compartment. And you have to look at comorbidities and decide what you have the best chance of fixing and go for that.
Nicola A. Hanania, MD, MS: Yeah, I agree with that. One other thing we didn’t talk about is oral steroid-dependent asthmatics, which seem to favor the anti—IL-5 therapy if they have high eosinophils. But certainly, anti–IL-4, dupilumab, has an indication now for oral steroid-dependent asthma.
Bradley Chipps, MD: It’s the only 1 that has an indication for that.
Nicola A. Hanania, MD, MS: Regardless of eosinophil count.
Bradley Chipps, MD: Right.
Nicola A. Hanania, MD, MS: With omalizumab, we had some data from the EXTRA study, which I led, to show some effect, but it’s not as strong of an effect.
Transcript edited for clarity.