Biologics in Asthma: Treatment Selection
APRIL 29, 2019
MD Magazine Staff
Neal Jain, MD, FAAP, FAAAAI, FACAAI: So we’ve alluded to this question, although I don’t know that I have pinned anyone down. We have these now 5 different options that are available, and we’ve talked about them in the context of bringing up these different biologics. But what are the factors that help us to identify which patient might be an optimal candidate for Xolair, omalizumab, versus an anti–IL-5 [anti–interleukin-5] therapeutic, of which there are 3, versus dupilumab? How do we define that?
Nicola A. Hanania, MD, MS: I think one thing we did not really talk a lot about is differentiation between the 3 anti–IL-5s that are available. Mepolizumab was the first to be approved. It’s a once-a-month option approved for patients age 12 and above.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: It’s a fixed dose.
Nicola A. Hanania, MD, MS: Subcutaneously. Reslizumab came next, and it’s an intravenous weight-based therapy. Some data suggest it may work better in obese patients. One has to say there are no head-to-head studies comparing any of these—all 5 of them. There are some analyses, meta-analyses, but again it’s very hard, and I think one has to be very cautious about comparing one versus the other. The patient populations are different. And then reslizumab is approved for patients age 18 and above as an intravenous infusion. Benralizumab is a bit different. It targets the IL-5 receptor. Hypothetically, it has a better effect on eosinophil death, but again there are no head-to-head studies. The drug is given every month for the first 3 months, but then every 8 weeks. So that may have an advantage in a way that it doesn’t have to be given every month, and it’s subcutaneous.
Having said that, the patient’s preference is important. Brad and I worked on a shared decision-making tool, and it’s online right now. Obviously, I’m biased. I think it’s a very important tool for patients to know about, especially if you have a patient who has overlapping features, who is allergic eosinophilic where there’s more than 1 choice. Patients can go in and read about these biologics so that they understand what they’re stepping into.
So the route of administration, the frequency, where to give it, the cost, the insurance coverage, where the patient has eosinophilia…. I think in patients who have no eosinophilia and allergic asthma, no question omalizumab remains the choice right now. In those with high blood eosinophils, and you can argue what is high—in general, 300 cells/mcL and above, but some people believe 150 and above—there’s more than 1 choice. In oral corticosteroid-dependent asthmatics, there’s more data to favor the anti–IL-5, anti–IL-4 than the omalizumab. All these have to be factored in when you decide. And the patient obviously also has a role when deciding on treatment.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: I think those are all absolutely the points that I consider. You had mentioned also comorbidities, and I’ve seen some posters here at AAAAI [American Academy of Allergy, Asthma & Immunology] that talked about this a little bit.
Bradley Chipps, MD: Low-hanging fruit, of course, with atopic dermatitis, which it’s obvious that it leads you toward an IL-4/IL-13 trend, inhibit that axis. Nasal polyps, probably IL-4/IL-13, although the anti–IL-5s, and probably omalizumab, have some effect on nasal polyps. And clearly, if you’ve got urticarial, you would probably mitigate toward omalizumab as a treatment option in those kinds of patients. But I think that the eosinophilic signal in the airway compartment is most affected, as Nic said earlier, by the IL-4/IL-13 molecule. And if that stays persistent, because it’s all affected so much by the IL-5s, you might want to use that as a therapeutic option.
Nicola A. Hanania, MD, MS: One thing one has to keep in mind with dupilumab: Although the clinical relevance is not known, but eosinophils tend to go up early on after administration. In the clinical trials, it was not of any consequence. But in real life, whether that would be a patient with very high blood eosinophils, whether that would be of concern, we still don’t know.
Bradley Chipps, MD: It may be a trafficking problem with the attacks. It tends to go back to, as you said, the baseline, about 16 weeks.
Aidan A. Long, MD: But it actually tells us something about the biology.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Teaches us.
Aidan A. Long, MD: You asked about the biomarkers, FeNO [fractional exhaled nitric oxide] and eosinophils. And you might think of them trending together. Here’s a clear example where they go in the opposite direction.
Bradley Chipps, MD: Unexpectedly, the opposite direction.
Aidan A. Long, MD: Yes. And so, we have stuff to learn. In terms of how you choose, the data are not there, obviously. We choose based on our experience. We’ve had some for a long time, some are new, and some are based on patient preference. We think about some of the issues that Nic mentioned, about whether eosinophilia is a big issue, and the comorbidities. And I think we’ll all do it differently eventually. Over time, it will become clear to us. But, in terms of providing guidance to our colleagues, I think we don’t have the tools to provide that kind of guidance.
Nicola A. Hanania, MD, MS: The one thing that I would be very cautious about is switching quickly. I think once a decision is done on a biologic…. I can tell you, from my experience, I have a patient who has already tried 3 of them because she wants….
Aidan A. Long, MD: She wants an immediate response.
Nicola A. Hanania, MD, MS: She wants an immediate response, and that’s not going to happen. Some response may happen, like lung function improvement with some of them. But to give a chance for the biologics to work….
Bradley Chipps, MD: Do you think 16 weeks is OK, or do you want longer?
Nicola A. Hanania, MD, MS: Well, some data from omalizumab from Europe suggests 16 weeks is good enough. That’s 3 months. I think at least 3 months, I would say.
Bradley Chipps, MD: Three to 6 months.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: And I think if you look at the clinical trials, although they’re in an optimized situation—the phase 2, phase 3 trials—we’re talking about 24 weeks, 52 weeks, 48 weeks weeks, right? So I think 3 to 6 months is a reasonable sort of approach.
Nicola A. Hanania, MD, MS: I think 16 weeks, which is 4 months. My math is not good.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Yes.
Nicola A. Hanania, MD, MS: So 4 months is pretty good. There is some suggestion from the United Kingdom for even 1 year of treatment. But it’s hard to believe that if patients are not responding in 1 year, that they will continue getting injections.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Especially if they’re having exacerbations. If you’re not able to sort of see them improve in lung function….
Nicola A. Hanania, MD, MS: See, that’s the problem with these biologics. Well, it’s not a problem. It’s really a challenge. How do you know if they’re responding?
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Where biomarkers would be nice, if we had predictive biomarkers and biomarkers that changed with therapy.
Nicola A. Hanania, MD, MS: So the blood eosinophils go down with anti–IL-5s. Certainly, the FeNO doesn’t change with anti–IL-5s, but it does go down nicely with anti–IL-4s. We’ve shown some data now recently with omalizumab. Some of these biomarkers go down. IgE [immunoglobulin E] doesn’t change, as you know. But there are some tools, like clinical assessment tools that are very subjective.
Aidan A. Long, MD: It brings up a very important point. The patients who were studied, in whom these drugs were effective, were clearly an exacerbation-prone phenotype. We all have severe asthmatics who have chronic symptoms, maybe not 2 exacerbations a year, in whom we’ve tried these drugs and then we say, are they working? It’s very difficult to know, because with the exception of dupilumab, lung function change was not a big feature of these drugs.
Bradley Chipps, MD: Reslizumab had a pretty good lung function change.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: I think the 3—reslizumab, and benralizumab, and dupilumab—all had decent, varying degrees….
Aidan A. Long, MD: We talk about choosing biomarkers to guide us. I think the clinical pattern is equally important in guiding us. If it’s not an exacerbation-prone phenotype, and is just chronic symptoms, that’s going to be hard to show.
Bradley Chipps, MD: PROs—patient-reported outcomes—are what patients want to see. They want to feel better.
Aidan A. Long, MD: Exactly. So it’s hard to judge. I have certainly had patients in whom mepolizumab appeared, at 3 months, to be not really doing much. But then by 6 months, it had turned around. I think maybe 6 months might be better than 3.
Bradley Chipps, MD: Especially if you’re treating a patient through the summer months. Their asthma is likely to be more quiescent during that time, and you really do need 6 to get to the fall to see how things are going.
Transcript edited for clarity.