Significance of the QUEST Trial in Asthma

This is part of the MD Magazine^® Peer Exchange, “Precision Medicine in the Treatment of Severe Asthma.”Click here for Segment 16 and learn about novel therapies under investigation in asthma.

Peter Salgo, MD: This is all part and parcel, it seems to be, of the “I hate steroids” club. They’re a blunderbuss. Let’s get something focused and laser-like, and do it right, right?

Neal Jain, MD: Absolutely.

Peter Salgo, MD: Scientific medicine. This is exciting stuff. This brings us to the topic of what’s coming next. I’ve got a feeling that this is just the tip of the iceberg. There’s more stuff in the pipeline. What are the QUEST findings with dupilumab?

Neal Jain, MD: QUEST is a phase III trial of a newer medication, dupilumab, which blocks IL-4 and IL-13.

Peter Salgo, MD: So those are the other 2?

Neal Jain, MD: Right. This phase III trial is really exciting. It demonstrated a rather significant improvement in a variety of measures in patients who were put on this medication, had moderate to severe disease, and were on high doses of inhaled steroids—some of whom were oral corticosteroid dependent. It demonstrated that it improved lung function, especially in those who had T2-high disease.

Peter Salgo, MD: This is the first time that I’ve heard this fairly definitively—it improved lung function.

Neal Jain, MD: It improved lung function.

Peter Salgo, MD: The others said, “Maybe in the long term.” Or, “We’ll take a look. Maybe it does. I’ll call you later.” Here you’re telling me that it does.

Neal Jain, MD: Right. It was interesting. If you looked at those who had the highest eosinophils and the highest FeNOs [fractional exhaled nitric oxide levels], the lung function improvement was the greatest.

Peter Salgo, MD: So the sickest got better the most?

Neal Jain, MD: Exactly. The most inflammatory got better the most.

Peter Salgo, MD: OK.

Neal Jain, MD: And it did reduce exacerbations. It decreased a lot of other things, including IgE [immunoglobulin E] levels, over time, and FeNO and eosinophils.

David Rosenstreich, MD: Nasal polyps, I think?

Neal Jain, MD: It did improve in those individuals who had significant polyposis. Nasal polyps, sinus disease—that also seemed to improve.

Peter Salgo, MD: How does it differ from the other drugs that are out there right now?

Neal Jain, MD: It’s a different mechanism. We’re looking at IL-4 and IL-13. There is some crossover with IL-5, but it’s a different mechanism. If you think about the inflammatory cells that are involved in this T2 process, eosinophils are certainly involved. They’re not unique to T2-high, but IL-4 and IL-13 are produced by a variety of inflammatory cells. It seems that if you were to graph this all out, it’s a huge mass. But IL-4 and IL-13 sort of have arrows going in every direction. For that reason, you see these kinds of results.

David Rosenstreich, MD: They’re one step upstream from IL-5. IL-5 is focusing on the eosinophil. This is going one step back, focusing on more general causes of the inflammation.

Peter Salgo, MD: But didn’t you guys warn me that fiddling with the immune system has its risks and that we might need IL-4, IL-13? Are you dicing with this stuff?

Neal Jain, MD: The data that have come out suggest that they’re extremely safe. We really haven’t seen any negative effects in the asthma population that has been treated with it. The data are coming out. We will see what happens, but it seems as though affecting this pathway has not proved deleterious.

David Rosenstreich, MD: When we give these drugs, we check for parasites. We measure Strongyloides antibodies. We have a big population from Central and South America. We have a lot of parasites, and we check for that because we don’t want to run into a problem with that. We make sure that older people have had their shingles vaccine because that’s a concern. We don’t give the live vaccine. So there are concerns. You have to be careful. You don’t want to use this indiscriminately. Be aware that we are interfering with the immune system and that you may need it for something. And so it’s not completely risk-free. You have to be on your guard.

Peter Salgo, MD: How many times have you seen strongyloidiasis?

David Rosenstreich, MD: Well, since you mention it, you haven’t read one of our more recent papers?

Peter Salgo, MD: No, I have not.

David Rosenstreich, MD: In our population, which is a big South American migrant population, we have a lot of people who have chronic strongyloidiasis. Some of them get steroids, and it flares up.

Peter Salgo, MD: I asked because I’ve seen it, and we warn the residents about it.

Neal Jain, MD: A single dose of ivermectin or something of that will treat it.

David Rosenstreich, MD: Exactly. It’s treatable.

Neal Jain, MD: We need to identify it.

David Rosenstreich, MD: Right. We identify it, and we treat it. It’s treated by one of the world’s safest drugs, which is ivermectin.

Peter Salgo, MD: Be aware of a disease in which residents go, “Whoa, that’s cool. I got to see strongyloidiasis.” No, you don’t want to see strongyloidiasis. It’s nasty stuff.

Raffi Tachdjian, MD: But going back to your point, IL-4 and IL-13 will act through this IL-4 receptor, the alpha subunit, specifically, and that’s where this mechanism is helpful in decreasing IgE and other B-cell—mediated output. But essentially, as Neal said, it’s reduction of exacerbation that we’re looking at and restoration of that patient’s asthma without hopefully using the corticosteroids and dealing with their side effects.

Neal Jain, MD: If you look at us, as allergists, this is where we get super excited. We get really nerdy when we start to look at IL-4 and IL-13 and the effects that we’re going to have. You think about what these cytokines do in affecting goblet cells and mucus production, in affecting smooth muscle and remodeling, and downregulating IgE and how that has an effect on dendritic cells and rhinovirus, and downregulating all these things that, over time, may have a significant impact. This goes back to, in the long term, does this change the trajectory and outcome and lung function decline?

Raffi Tachdjian, MD: Including eosinophilia.

David Rosenstreich, MD: To make a non-nerdy comment, the nice thing about dupilumab is that it’s already available. We have experience using it for atopic dermatitis. It works very, very well in a disease where we had no treatments before. That was a big problem. The results are quite remarkable. And so we have a good experience with it, it works well, people use it, and it has a very low side effect profile.

Transcript edited for clarity.