Use of Dupilumab in Treatment of Asthma

EP: 1.Overview of Asthma

EP: 2.Role of Type 2 Inflammation in Asthma

EP: 3.Signs of Severe Asthma and the Underlying Pathophysiology

EP: 4.Multidisciplinary Care for Patients With Asthma

EP: 5.Predicting Exacerbation of Asthma

EP: 6.Treatment Landscape of Asthma

EP: 7.Treatment Selection for Severe Asthma

EP: 8.Use of Guidelines to Classify Asthma

EP: 9.Overuse of Oral Corticosteroids in Asthma

EP: 10.Use of Biologic Treatment in Asthma

EP: 11.Dual Inhibition of Interleukins by Dupilumab in Asthma

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EP: 12.Use of Dupilumab in Treatment of Asthma

EP: 13.Optimizing Biologic Treatment Selection in Asthma

EP: 14.Switching Biologic Treatment in Asthma

EP: 15.Trends in Biologic Treatment of Asthma

EP: 16.Role of Biomarkers in Asthma

EP: 17.Final Thoughts on Treatment of Asthma

Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI: Dupilumab is indicated for patients aged 12 and over who have eosinophilic asthma or oral corticosteroid-dependent asthma. From the trials, it was apparent that those with high T2 [type 2] inflammatory markers tended to do better, even though the requirement is an eosinophil count of 150 cells per mm3 peripherally or greater. Dr Siri, can you deep dive into this area to guide us through some of the papers and results that made this come about?

Dareen D. Siri, MD, FAAAAI, FACAAI: The pivotal trials, at least in the adolescent age group 12 and up, were published in the New England Journal of Medicine. The first study we’ll talk about is Dr Mario Castro’s study. This 1 was ages 12 and up, and it was a placebo-controlled, double-blind clinical trial, which was randomized. It involved 1900 patients who had moderate to severe asthma with a baseline eosinophil count of at least 150 cells per mm3. We haven’t talked about that, but that’s easy to calculate for a primary care audience. If on a CBC [complete blood count] with differential is 0.15, that’s 150 cells per mm3. It’s pretty easy to move that decimal point over. That number is in the normal range. If a patient has normal eosinophils, that doesn’t mean they’re not a candidate for these medications.

Going back to Dr Castro’s study, published in 2018 in New England Journal of Medicine, it looked at the 52-week outcomes—most importantly exacerbation rates but also at forced expiratory volume in 1 second [FEV1], improvement in lung function, quality-of-life scores, and so forth. These patients all received standard-of-care treatment, including inhaled corticosteroids, long-acting beta-agonists, and additional controllers if needed. Some of those patients could have been eosinophilic. Some had used steroids as well systemically. After 52 weeks, this demonstrated positive outcomes compared with a placebo. All patients were on standard-of-care treatment in terms of things I talked about—exacerbation rates, lung function, quality of life. That was a positive study.

In the same year, also in the New England Journal of Medicine, a publication by Dr Klaus Rabe looked at adolescent patients aged 12 years and up. It was 210 patients. In this study, they looked at patients who were corticosteroid dependent. Those patients had eosinophil counts of 150 cells per mm3 or greater. They also had an fractional exhaled nitric oxide of at least 20 parts per billion, which is considered abnormal or inflamed. They also looked at a subset of patients in that group who had 300 cells per mm3 of eosinophils on their CBC with differential. Looking at the 2 different subgroups, the second was a post hoc analysis.

The primary end point in that 24-week study was after an optimization period. All the patients came in on corticosteroids, so they had to optimize them to get them to the lowest amount that the patients could tolerate without having exacerbations. After that optimization period, the patients were randomized. This was a randomized double-blind, placebo-controlled trial. The primary end point was a reduction in oral corticosteroids and how many patients could get to 5 mg or less, besides percentage of reduction, which hopefully was at least 50%. You can see from the table in the slides that all those end points were met in terms of oral corticosteroid reduction compared with placebo, which was significant. They achieved 5 mg or less. The most significant grouping was those with eosinophil counts greater than 300 mg. But it was also effective in patients who had eosinophil counts of 150 cells per mm3 or greater plus a fractional exhaled nitric oxide of at least 20 parts per billion. That’s very exciting. Both studies, LIBERTY ASTHMA QUEST and LIBERTY ASTHMA VENTURE, led to approval in patients 12 years and older with moderate to severe asthma.

Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI: You brought up a very important point about peripheral eosinophil count. I’ve seen counts of 800 cells per mm3—0.800—that are still not flagged by almost all labs. It’s the job of the astute immunologist-allergist to point that out and then figure out if is this part of that bigger picture of severe asthma or eosinophilic asthma. Let’s not forget that some of these counts have to be reduced because these patients are all high-dose inhaled corticosteroids or oral steroids. That’s another layer of complexity that’s tougher for the primary care physician to delve into, as our experience has shown. It takes a little more training and experience to get to that point. For the newer indication or approval of patients with severe asthma or who are eosinophilic, who are oral corticosteroid dependent from 6 to 11 years of age, walk us through that approval process.

Nicole Chase, MD, FAAP, FACAAI, FAAAAI: Another point is that if you look at the indications for these different biologics, the only 1 that has severe but also moderate asthma is dupilumab. That’s another thing that you pointed out, Dr Siri, that’s helpful to remember.

Dareen D. Siri, MD, FAAAAI, FACAAI: With any medication, we want to talk about safety. Because eosinophils are the talk of this discussion, some safety points have come out of clinical trials, so we want to make sure these are tolerable. Indeed, dupilumab was tolerable in this group of patients with moderate to severe asthma. In both studies, 5% to 15% of patients developed transient eosinophilia. That means the eosinophil counts will increase and then over time, with continued treatment and no intervention, they’ll decrease back, similar to baseline levels. This is a benign condition that we’ve noticed. On the label, it’s not required for us to follow the CBC with differential and look at those eosinophil counts. We have to recognize that this occurred in a proportion of patients, and it may be an adverse effect that we notice, but it’s considered a benign condition that requires no intervention. In the context of that individual patient, we have to think about adverse effects when we talk about this.

Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI: As some of you know, transient increases are due to these eotaxins, which is the lack of the ability of the eosinophils to get to the tissue to do their damage or inflammatory effects. But there’s no guideline, and there’s no indication to monitor these patients, at least serologically, once you start them.

Dareen D. Siri, MD, FAAAAI, FACAAI: Thanks for pointing that out. If somebody is wondering why this occurs, it’s because of the mechanism of action of dupilumab blocking IL-4 and IL-13. Thus, eosinophils can’t migrate to where they need to be.

Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI: Taking it a step further, for 6- to 11-year-olds and the approval that just happened a couple of years ago for dupilumab for eosinophilic asthma, dive into that as well.

Dareen D. Siri, MD, FAAAAI, FACAAI: For the 6- to 11-year-old age group study, the lead author was Dr [Leonard] Bacharier in 2021. This was called the VOYAGE study, and it studied about 408 patients, 6 to 11, with moderate to severe asthma. This was a randomized double-blind, placebo-controlled trial. During this study, the patients were still on standard-of-care treatment. Some had eosinophilic asthma, and some were steroid dependent, so a variety of children came into the program. They were looking at similar outcomes to the adolescent-and-up trial, which showed exacerbation rate reduction, FEV1 or spirometry improvement, on the Asthma Control Questionnaire, which includes spirometry and quality of life. Those all were clinically meaningful. In terms of safety, it was very similar to the adolescent-and-up trials. There wasn’t anything exciting or new; it was very consistent. Both demonstrate efficacy in this age group, which we had very few options for before in terms of type 2 inflammation and demonstrating a similar safety profile. It addressed that need very well.

Transcript edited for clarity