COMMENTARY

Eosinophilic Asthma: Reducing Exacerbations and Steroid Use

Andrew F. Shorr, MD, MPH

Disclosures

January 28, 2015

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This is Andy Shorr from Washington, DC, with the pulmonary literature update. Today I want to highlight a recent article in the New England Journal of Medicine by Ortega and colleagues,[1] who reported the MENSA trial.

This study focused on the use of a novel humanized monoclonal antibody against interleukin-5 (IL-5) in patients with severe eosinophilic-related asthma. We all take care of patients who, despite optimal inhaled therapy and the use of other oral agents, still suffer frequent exacerbations. Even after we have ruled out confounding syndromes such as vocal cord dysfunction or allergic bronchopulmonary aspergillosis, we are left with this cohort for whom we have very few options. These patients are frequent users of healthcare and they are often taking oral corticosteroids.

These investigators studied the use of a novel monoclonal antibody to attack severe asthma in this cohort of patients. This was a three-arm, randomized controlled trial that included a placebo group, a group that received the drug intravenously at 75 mg, and a group that received the drug subcutaneously at a dose of 100 mg. The drug and placebo were administered every 4 weeks for 32 weeks.

Narrow Study Population

The study participants comprised a very specific population of patients. All patients had to have a history of at least two exacerbations and substantial variability in their air flow, confirming the diagnosis of asthma. In addition, participants had to have biologic evidence of eosinophilic activation, requiring ≥ 150 eosinophils/µL in a recent complete blood count or ≥ 300/µL at some point previously. Thus, it was a very narrow cohort of patients.

The natural history of this disease is that some patients improve and their therapy can be reduced or stepped down. For this reason, the study design also included a run-in period during which patients were watched for several weeks before being randomly assigned to a treatment. Finally, this study required that these patients be receiving the equivalent of high-dose inhaled corticosteroids. Again, this was a very narrow population, requiring last-line therapy—a very specific phenotype that is enriched by hematologic biomarker.

Patients were randomly assigned to one of the three arms previously described. The primary endpoint was patient-centered and clinically relevant: the rate of exacerbations. Secondary endpoints included the rate of exacerbations that led to hospitalization or emergency department visit, change in forced expiratory volume in 1 second (FEV1), and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5).

The study was double-blind, so the adjudication of the exacerbation was not affected at all by the treatment the patient was receiving. Similarly, all patients kept very clear diaries explaining what was going on so investigators could externally validate exacerbations. Exacerbations also required that the patients receive oral or systemic corticosteroids for at least 3 days.

The actual study population was significantly ill with asthma. Many had experienced more than three exacerbations. The FEV1's were in the mid-60s across the board. On average, the mean eosinophil count was about 300 cells/µL. Again, this was a unique population of patients with hard-to-control asthma.

Study Outcomes

In terms of the primary endpoint, intervention with the study drug—whether 75 mg IV or 100 mg subcutaneously—was associated with substantial reductions in the rate of exacerbations, for an approximately 50% relative risk reduction. The absolute risk reduction was somewhat smaller because this was a short-term study, but it was also significant. In addition, all of the secondary endpoints, including exacerbations requiring hospitalization or ED visit, patient quality of life, flow changes in terms of FEV1, were improved with the intervention.

This suggests that anti-IL-5 approaches are important in the pathway of asthma in these patients and that there are clearly distinct phenotypes of asthma that are biologically mediated. Thus, asthma is not one common disease but a syndrome that probably reflects a series of other factors, which is consistent with what we have learned about asthma biologically over the past two decades.

This study is associated with the COMPANION study,[2] which was published in the same issue of the New England Journal of Medicine. This latter study looked at the ability of this anti-IL-5 molecule to help patients with asthma reduce and even discontinue oral corticosteroids. The study showed positive results in a very narrow group of patients.

Both studies suggest that we are making advances in understanding what is going on in asthma. If and when these molecules are approved, we clinicians will be required to be more thoughtful about not lumping everyone who has what we think is asthma into one bucket. Rather, we will need to categorize these patients according to how their disease behaves over time and with our observations and interventions.

I urge you to look at the MENSA trial, published in the New England Journal of Medicine. This is Andy Shorr from Washington, DC.

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