Precision Medicine in the Treatment of Severe Asthma - Episode 12

Biological Therapy for the Treatment of Asthma

This is part of the MD Magazine® Peer Exchange, “Precision Medicine in the Treatment of Severe Asthma.”Click here for Segment 13 and learn about using biologic therapy in patients with asthma.

Peter Salgo, MD: Give me a quick overview of the clinical trial successes and failures with therapies that are now directed to these known bad actors—IL-4, IL-5, and IL-13.

Neal Jain, MD: I would start with IL-5. In the initial studies looking at anti—IL-5 therapy and IL-5 being important in the eosinophil recruitment and survival, if you just took everyone who didn’t necessarily have eosinophilic or T2-high disease, there were failures. They didn’t see a good response in those initial trials. They then said, “Well, let’s get a little bit smarter. Let’s look at the subgroups of these individuals.” They found that those individuals who had eosinophilic disease, especially those who had a lot of exacerbations, seemed to respond really well to anti–IL-5 therapy. Then they sort of asked, “What are the other pathways?” IL-4 and IL-13, right? Some people said, “I don’t know if blocking both IL-4 and IL-13 is a good idea, because there’s a lot that happens with those 2 cytokines in our immune system. Let’s target IL-13. If we just target one of these pathways, maybe we’ll see a less potentially deleterious effect.” Unfortunately, targeting just IL-13 wasn’t enough. It didn’t hit enough. We didn’t see success.

David Rosenstreich, MD: I think we should see what’s available now.

Peter Salgo, MD: I was just going to start that conversation.

David Rosenstreich, MD: Right now, we have omalizumab, anti-IgE [anti—immunoglobulin E], which was really the first monoclonal antibody for use in asthma. That seemed to help a subpopulation of patients. It was targeted for people with an Ig [immunoglobulin] level between 30 and 700, so we had some constraints. It seems to reduce asthma exacerbations but doesn’t seem to change pulmonary function very much. It is a fairly good drug. Some people who are on it are doing very well.

Now we have the anti—IL-5 agents. There are 3 of them that are now available. Focusing on the eosinophilic phenotype appears to be important for these.

Peter Salgo, MD: Let’s run through them. By the way, omalizumab is for people who are older than 6 years of age?

David Rosenstreich, MD: Right.

Peter Salgo, MD: There are 3 IL-5 inhibitors. We might as well run through them. There’s mepolizumab, reslizumab, and benralizumab. Can you compare these drugs and talk me through some of this?

David Rosenstreich, MD: Well, they’re all anti—IL-5s, in some way. Two of them are subcutaneous.

Peter Salgo, MD: Which ones?

David Rosenstreich, MD: Mepolizumab and benralizumab are both subcutaneous, once-a-month options, usually. Reslizumab is also an anti—IL-5. It is intravenous. Because they’re fixed doses (the subcutaneous drugs), for people who are very obese, we tend to use the intravenous drug. It’s dose dependent and it’s dosed on weight.

Peter Salgo, MD: And that’s reslizumab?

David Rosenstreich, MD: Reslizumab. You’re able to actually give people more, and they seem to do a little better.

Neal Jain, MD: Benralizumab, because it binds to the IL-5 receptor rather than acts as an IL-5 analogue, depletes the eosinophils to a far greater extent. And so it doesn’t seem to be weight dependent.

David Rosenstreich, MD: I personally don’t have that much experience with it. Do you?

Neal Jain, MD: Yes, I’ve had some experience. It is dosed as an every-other-month option after the first 3 doses, so there are some advantages from a dosing perspective.

Peter Salgo, MD: Going back to omalizumab, you said something interesting. You said it doesn’t necessarily produce changes in lung function.

David Rosenstreich, MD: Right.

Peter Salgo, MD: So what does it do?

David Rosenstreich, MD: It reduces steroid use and reduces exacerbations in clinical trials. A lot of these drugs don’t necessarily improve lung function when you measure FEV1 [forced expiratory volume in 1 second].

Neal Jain, MD: Not quickly. Again, with omalizumab, if you look at the most severe exacerbation-prone individuals, especially in kids, there are some data to suggest that over time there is improvement. It’s not quick, especially with omalizumab. With benralizumab, there is a rather significant and rapid increase in lung function within the first month or two of therapy. With the others, it’s more modest. It’s not dramatic. It’s 100 to 200 milliliters, depending upon your phenotype. If you’re a higher-eosinophil, higher-exacerbation-prone individual, you do see a greater improvement in lung function and greater improvement in reduction of exacerbations.

David Rosenstreich, MD: The thing with omalizumab, as far as I know, is that we don’t really have good phenotypes or biomarkers for it. Some people respond, and some people don’t. We’ve never been able to figure out who those people are. A lot of people get it, and not everyone does so well. And with the newer medications, we have better markers. We can phenotype them better. We can target things better, in terms of who’s going to benefit. This makes a big difference with these very expensive drugs.

Raffi Tachdjian, MD: Regarding lung function, the mechanistic underlying pathway is the metalloproteinases that are affected. That makes way for this irreversible lung obstruction and change. Corticosteroids have not been able to change that. This is an interesting part in our history now—to see this forward, long-term observation, to see if some of these molecules will actually help reverse asthma.

Peter Salgo, MD: To reverse asthma?

Raffi Tachdjian, MD: Correct.

Peter Salgo, MD: Now, are you talking about reversing the lung injury—reversing permanent lung dysfunction?

Raffi Tachdjian, MD: Lung function starts declining the minute that we’re born. It’s like a Kaplan-Meier survival curve. We want to hold for as long as we can, at 99 or 98, to try to minimize that decline. Corticosteroids—that’s been part of the reason for being hesitant about using them. But that was our only option. Now we have more of these targeted therapies and we can see if we can actually improve that survival of the lung. Long term, because we don’t have that many years of data yet, maybe we can actually start reversing the decline from the lungs?

Peter Salgo, MD: The reason I stopped right here is because this is the first time I’ve ever heard that for a biologic—for an agent.

Neal Jain, MD: There are a lot of what-ifs right now. It’s exciting, as David had mentioned, for us to sort of look at where we could go with some of this. We do start to lose lung function as soon as we pass adolescence.

Peter Salgo, MD: I like your answer better. He said after we’re born. You said adolescence.

Neal Jain, MD: After adolescence. We grow, and we grow, and we grow. And then we stop growing. And then it starts to decrease. There’s a more rapid decrease in lung function in those patients who have a lot of exacerbations. And unfortunately, despite the use of steroids, we still see patients having exacerbations. What’s interesting is with Xolair, first, and now with some of these other medications, we’re seeing an impact on exacerbations, which are primarily driven by viruses. We’re starting to understand a little bit about the immunology of how that works. But by impacting and stopping those exacerbations, you see a flattening in the decrease in lung function, which approaches what you see in normal individuals.

Transcript edited for clarity.