Anti-IL4/IL13 Antibody Dupilumab is Effective in Asthma with Elevated Eosinophil Levels

Asthma remains poorly controlled in as many as 20% of patients who use combination therapy of inhaled glucocorticoids (ICSs) plus long-acting beta-agonists (LABAs).

Mainstays of the management of difficult-to-control asthma include:

- increased adherence to treatment
- avoidance of allergens and other exacerbating factors
- control of common coexisting conditions such as gastrointestinal reflux (GERD), postnasal drip, and sinusitis

Adjuvant therapies include:

- leukotriene modifiers, mostly the generic montelukast
- theophylline
- anti-IgE antibody (omalizumab, Xolair)
- bronchial thermoplasty
- systemic glucocorticoids
- tiotropium -is not approved by the FDA for treatment of asthma



Severe asthma - differential diagnosis and management (click to enlarge the image).

Studies have shown efficaty of new asthma treatments that target cytokines that play a role in the pathogenesis of asthma such as including anti–interleukin-5 (mepolizumab) and anti–interleukin-13 (lebrikizumab).

This study evaluated the efficacy and safety of dupilumab, a human monoclonal antibody to the alpha subunit of the interleukin-4 receptor in 52 patients with asthma. Dupilumab inhibits signaling by both interleukin-4 and interleukin-13 which "work" through the same receptor unit.

The study population included patients with persistent, moderate-to-severe asthma and elevated eosinophil levels (a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3%). All patients were treated with inhaled glucocorticoids (ICSs) plus long-acting beta-agonists (LABAs) at the beginning of the study.

Dupilumab (300 mg) or placebo were injected subcutaneously once a week for 3 months. Patients stopped LABAs at week 4 and stopped ICSs during week 6-9.

There was an 87% reduction in risk of asthma exacerbation with dupilumab (odds ratio, 0.08). Improvements were observed for most measures of lung function and asthma control.

Editor's note: It is not possible to calculate the number needed to treat (NNT) as the absolute risk reduction was not reported by the NEJM.

The study authors concluded that in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels who used ICS/LABAs, dupilumab therapy was associated with fewer asthma exacerbations when LABAs and inhaled glucocorticoids were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers.

At first glance, the response to dupilumab therapy is outstanding, with an 87% reduction in the proportion of patients with an asthma exacerbation. However, the study shows efficacy only in a limited subpopulation of patients with asthma. Only 21% of those screened for the study met the inclusion criteria. We do not know whether dupilumab will be effective in the much larger population of patients who use ICS/ LABAs and do not have eosinophilia. Dupilumab is able to substitute ICS/LABAs in a specific subgroup of patients with asthma. However, we do not know if it offers any benefit of the patients had stayed on ICS/LABAs.

The study was funded by the dupilumab manufacturers Sanofi and Regeneron Pharmaceuticals.

Editor's note: Dupilumab is not the "magic bullet that cures asthma". This study included a selected group of patients with elevated eosinophils. Not all patients with asthma have elevated eosinophils. Another monoclonal antibody, mepolizumab, anti-IL5, has been shown to help patients with eosinophil-predominant asthma. Yet another monoclonal antibody,lebrikizumab, anti-IL13 helps patients with asthma and elevated periostin level. It is becoming clearer that as we get better at defining different asthma phenotypes based on biological markers (eosinophils, periostin, etc.), we may be able to offer targetted therapy to selected patients that fullfill the criteria for efficacy. These antibodies would not help all patients with asthma. In addition, the monoclonal antibodies require an injection and are very expensive. It is important to determine the number needed to treat (NNT) in order to make a cost-benefit analysis of such treatments.

References:

Dupilumab in Persistent Asthma with Elevated Eosinophil Levels — NEJM http://bit.ly/14xiFF8
Inhibiting Interleukin-4 and Interleukin-13 in Difficult-to-Control Asthma — NEJM http://bit.ly/14xfQnk

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