Dupilumab: Mechanism, Dosing, and Pivotal Trials

Peter L. Salgo, MD: We’ve jumped forward into dupilumab. Let’s define it. It’s a recently approved drug, right?

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: Approved for asthma.

Peter L. Salgo, MD: Moderate to severe asthmas.

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: It was approved for atopic dermatitis about 2 years ago.

Don A. Bukstein, MD: Yes, it has been approved for atopic dermatitis.

Peter L. Salgo, MD: OK. What is its mechanism of action? How does it differ from other drugs?

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: Well, it blocks, as John has mentioned, IL-4 and IL-13. In the cytokine family, there’s a lot of redundancy. So you block 5, and then maybe 8 does something similar. In this case, 4 and 13 have similar mechanisms, ultimately leading to the production of IgE [immunoglobulin E], which is the immunoglobulin that causes allergy. So this drug has been shown to fairly effectively block both of those pathways, which takes it higher up in the inflammatory pathway, whereas the IgE blocker omalizumab is much lower in the pathway.

Peter L. Salgo, MD: Where does dupilumab fit in the treatment algorithm for asthma? Does it have its own niche? Is it instead of something?

John J. Oppenheimer, MD: Your question is a good one. We’re befuddled. We don’t have an answer because these medicines really look at the same thing. They’re treating that same phenotype, the T2 [type 2] high.

Don A. Bukstein, MD: That’s right.

John J. Oppenheimer, MD: Each has subtle differences. You mentioned benralizumab every 2 months. Dupilumab can be given at home. Each one is a little bit different.

Don A. Bukstein, MD: Which may be a problem.

John J. Oppenheimer, MD: Every 2 weeks.

Don A. Bukstein, MD: Every 2 weeks, but it may be a problem, John.

John J. Oppenheimer, MD: Adherence.

Don A. Bukstein, MD: You know, adherence. At least with the other biologics—these are expensive medications—we’re overseeing. They’re coming to our office as allergists. That’s one of the reasons I don’t like infusion centers. I would much rather have that patient coming in where we can reinforce proper use so we can be enthusiastic about their ability to control their disease. We’re kind of cheerleaders, whether it’s us or our staff. So it’s really important to me that I see them. If what you’re saying is that at-home use may be a problem with adherence, it occurs to me that at-home use might be very nice for adherence.

John J. Oppenheimer, MD: I mean, there are some people, obviously, who live a great distance from your practice or clinic.

Don A. Bukstein, MD: Right.

John J. Oppenheimer, MD: This could be a game changer. And I think there are going to be innovative ways to assure adherence with smart injectors in the future.

Peter L. Salgo, MD: Injectors snitching on their patients.

Don A. Bukstein, MD: No, absolutely. There’s more of a chance that this is going to be a positive than a negative. It’s just a warning that it may not always be positive for every patient.

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: All you have to do is have one of your staff scheduled—telemedicine—and call the patient every 2 weeks and say, “Did you take care it?”

Don A. Bukstein, MD: Absolutely.

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: There’s evidence that works with allogeneic therapy.

Peter L. Salgo, MD: If I had a drug I could take at home and didn’t have to go to the doctor’s office or the pharmacy, I’d like that.

Don A. Bukstein, MD: Sure.

Louis Christos, RPh: And you will see that with the IL-5s.

John J. Oppenheimer, MD: Correct.

Don A. Bukstein, MD: Yes.

Louis Christos, RPh: They are both working on self-administered subcutaneous formulas.

Don A. Bukstein, MD: Yes, and I think there may be a middle ground—telemedicine—whether in the pharmacy or at home, just watching the patient every 2 weeks administer and see whether they have any problems. So there are ways around that.

I’m for actually thinking about giving dupilumab and others in the pharmacy. We give lots of injections in the pharmacy. These have very low risk, and at least that way you can track the disease. Kind of like a telepharmacy visit.

John J. Oppenheimer, MD: Well, you talked a little about your adherence devices. You have them also for injectors.

Don A. Bukstein, MD: That’s right.

John J. Oppenheimer, MD: I think it’s going to be an exciting next 5 to 10 years. We’re going to move to the next generation.

Peter L. Salgo, MD: Talk about the 2 trials. There’s the QUEST trial; there’s the VENTURE trial. What are these things? People have been talking about them. What are these trials?

John J. Oppenheimer, MD: Well, there are 2 trials; they are the pivotal trials. And one, the QUEST trial, involved looking at a group that was on inhaled medicines to see whether they benefited. This is a population that had fairly frequent exacerbations. And they looked to see whether adding dupilumab would translate to better outcomes.

Don A. Bukstein, MD: For all-comers.

John J. Oppenheimer, MD: All-comers. And it did. There was also the VENTURE study done, almost in tandem, we’ll say, in which they looked at people who were oral steroid dependent—the most difficult of our patients with asthma. And they were able to show that they were able to reduce oral steroids by adding dupilumab and actually showed increased improvement in their control levels above and beyond. So it’s a double whammy.

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: And there was a marked improvement in FEV₁ [forced expiratory volume in first second of expiration]. If I remember correctly, it all started about 1 month after treatment. It was very rapid onset.

Don A. Bukstein, MD: This one—well, they all work quickly. But dupilumab really seemed to have very rapid onset of action, not a lot of adverse effects, given at home, all-comers, and FeNO [fractional exhaled nitric oxide] was a very good marker. In fact, it was a super good marker in following improvement.

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: I don’t remember that.

John J. Oppenheimer, MD: To make this as clear as mud by the way, their eosinophil counts transiently went up in the beginning.

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: Yeah, there you go.

Peter L. Salgo, MD: Thank you for that. That’s the strangest….

Don A. Bukstein, MD: Just to really confuse you.

Peter L. Salgo, MD: Give me an optimum patient for dupilumab. What’s the right one? We talked about the right patient for some of these others.

Don A. Bukstein, MD: Well, the first thing is their insurance company. This is a very new drug. It’s just been approved by the FDA. It takes a while for insurance companies and payers to cover. But I would say—John said it before, and Linda did, too—it’s that patient who probably has positive skin tests, probably has an elevation in IgE, because they have positive skin tests, probably has somewhat of an elevated eosinophil count, and maybe not 400 or 500, and may or may not have atopic dermatitis. When we did the studies, I was amazed at its effect on the upper airway. I think chronic rhinosinusitis types of symptoms with nasal polyps are probably going to respond very, very well for this drug.

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: And that was one of the biggest challenges in the allergy practice in that patient population.