Identifying the Biomarkers for the Treatment of Severe Asthma - Episode 12
Neal Jain, MD, FAAP, FAAAAI, FACAAI: We’ve talked a little bit about the approved agents. We’ve sort of touched on all of them. Does anyone want to touch a little bit more on the mechanism of action of dupilumab for moderate to severe asthma? We’ve heard about IL-4 [interleukin-4] and IL-13. What do we think about that?
Nicola A. Hanania, MD, MS: Dupilumab is the latest biologic to be approved by the FDA, and it targets the IL-4 receptor. We’ve done studies with targeting IL-13 before with lebrikizumab, which unfortunately was not as effective. Although it did reduce exacerbations, one study was strongly positive and the other wasn’t. So it sounds like targeting just IL-13 may not do it. The IL-4 receptor is a common receptor for both IL-4 and IL-13. So they’re really targeting both IL-4 downstream signaling and IL-13 downstream signaling. As we mentioned earlier, IL-4 is very important upstream in the switching and IgE [immunoglobulin E] production. IL-13 is a pleiotropic cytokine. It has several important roles in remodeling, mucus production, and eosinophilic recruitment, potentially.
Dupilumab data from a large phase 3 trial showed that it decreases exacerbations and improves lung function quite significantly within 2 weeks in patients with history of exacerbations, or moderate to severe asthma. This signal is seen more often in those patients with high blood eosinophils at baseline and high FeNO [fractional exhaled nitric oxide]. Currently, it’s approved for patients with eosinophilic asthma. But a subsequent study of steroid-dependent patients, the LIBERTY ASTHMA VENTURE study, shows that it does actually reduce exacerbations and improves lung function in that subpopulation. And the other unique thing about dupilumab is it’s every 2 weeks, but it’s approved to be given at home. We still need to figure out how that works. I wonder if any of my colleagues have experience? As opposed to the others, where they’re given….
Bradley Chipps, MD: Reslizumab just got home administration, too.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Is that a good thing or a bad thing, with your questions about adherence and patients may be feeling better?
Bradley Chipps, MD: It depends on the patient.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Right.
Nicola A. Hanania, MD, MS: Well, hearing my colleagues’ different feedback, I get that there is concern about compliance if it’s given at home. How do you know a patient got it or not? But certainly for patients, they don’t have to come in every 2 weeks. And so, that really is helpful as well.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: I think when you look at these therapies, especially with dupilumab, when people start to wash out therapy, their asthma comes right back. I think that that is generally what we’re seeing in this truly severe population of patients. It’s not like it magically fixes their asthma. I don’t think any of these, unfortunately, do that.
Nicola A. Hanania, MD, MS: They need to have long-term studies to see if there is any disease modification. There’s some interesting data from the dupilumab studies suggesting that the decline in lung function over the year compared to placebo is actually attenuated.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Right.
Nicola A. Hanania, MD, MS: Now, if you follow them for 4 years or more, whether that continues, we don’t know. But right now, none of these biologics have shown definitively a disease modifying effect. Even with omalizumab, when you stop it, patients can exacerbate.
Aidan A. Long, MD: So to get to your point about home use, dupilumab was previously approved for atopic dermatitis, eczema. So we have some experience with that. First, the patients appear to like it—not having to come in. They don’t necessarily take it every 2 weeks. They take it as they think they need it. So that will probably happen in asthma as well. It does raise a concern. With the in-office injectables like omalizumab, they were obligatorily seen and we could somehow monitor disease activity and monitor adherence. We’re not going to have that much opportunity with this, so it will be very interesting to see how that works out.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: I think certainly you’ll see those patients who have more severe disease probably being more adherent, which is what I think we see in the atopic dermatitis population. I think one of the concerns with home administration is if someone is being on/off therapy, could there be development of antidrug antibodies, or those kinds of things that might mitigate the effect of the medication? And I think that’s a valid concern that we just don’t have enough data on from these blinded controlled studies where there wasn’t that opportunity….
Aidan A. Long, MD: Exactly.
Nicola A. Hanania, MD, MS: I think real-world studies always help us because they do test these drugs in the real world. Patients who have other comorbidities have been excluded from clinical trials.
Bradley Chipps, MD: A colleague used to say that there were people above and below the line, and those who are on one side or the other may do fine every 4 weeks versus every 2 weeks, where the others won’t, and you’ve got to treat each individual patient.
Aidan A. Long, MD: Nic spoke about the mechanism of action of dupilumab. It’s a shared receptor between IL-4 and IL-13. And Brad spoke about the comorbidities. This seems to be an interesting biologic. It seems to have a pretty broad anti—type 2 disease effect. And I think we’re going to learn an awful lot about type 2 diseases from this.
Bradley Chipps, MD: It’s got a bigger net than the other drugs.
Aidan A. Long, MD: One of the beauties of the biologics is that they do teach us about the diseases we all treat. We spoke about the antiviral effect of this anti-IgE drug. That was not predictable. So we will learn a lot more about our diseases.
Bradley Chipps, MD: Until the ICATA study published figure 2 in the paper that showed the fall and spring, nobody thought of it. Nobody thought of it.
Transcript edited for clarity.