2018 Section 5 - Rhinology and Allergic Disorders

CASALE

J ALLERGY CLIN IMMUNOL VOLUME 139, NUMBER 5

FIG 2. Mechanism of action of dupilumab. Dupilumab binds to the IL-4 a chain prohibiting either IL-4 or IL-13 from binding and subsequent signaling through the STAT6 pathway.

year, FEV 1 <65% of predicted value, use of beclomethasone >_600 m g/d, and long-acting b -agonist use), this rate reduction was more pronounced. This reduction in exacerbation rates com- pares favorably with those found with other biologics aimed at type 2–high asthma in similarly selected patients. However, it should be noted that even in an enriched patient population, oma- lizumab often does not show clinically meaningful improvements in lung functions in contrast to the other biologics discussed below. In case reports and small case series, omalizumab has also been shown to be effective in patients with nonallergic asthma. 12-15 It is not clear whether the patients had high blood eosinophil counts in these reports. Another anti-IgE mAb, ligelizumab, with approximately 50- fold greater affinity for IgE has been shown to inhibit allergen- induced skin test responses and reduce IgE levels to a greater degree than omalizumab. 27 However, in a field study of asthmatic patients, it did not have any better effects than omalizumab, and further development for asthma has been discontinued ( https:// www.novartis.com/our-work/research-development/clinical-pipe line ). IL-5–blocking strategies. High eosinophil counts can persist in patients with severe asthma receiving multiple controller medications, including corticosteroids. Furthermore, patients with persistent asthma and high blood eosinophil counts have more frequent exacerbations. 41,42 IL-5 is an important cyto- kine in eosinophil biology, promoting eosinophil differentiation, chemotaxis, activation, and survival. 43 Thus blocking the effects of IL-5 should prove useful in asthmatic patients with eosinophilic inflammation. Three bi- ologics using 2 different approaches have been studied in patients with severe asthma and eosinophilic inflammation ( Fig 3 ). FIG 3. Anti-IL-5 stategies. Reslizumab and mepolizumab bind to IL-5 whereas benralizumab binds to the IL-5 a chain preventing IL-5 from binding and mediating antibody-dependent cell mediated cytotoxicity of cells bearing this receptor.

IgE levels were decreased, with better clinical effects at dosages that reduced IgE levels by 90% or more. 8 This suggests that sub- stantial reductions in IgE levels are necessary to bring about a clinical response. Omalizumab was approved in 2003 by the FDA for patients with moderate-to-persistent allergic asthma that was not well controlled on current therapy. Until relatively recently, bio- markers to predict the responsiveness of patients to omalizumab were not identified. Hanania et al 9 analyzed data from the EXTRA study and found that omalizumab was more efficacious in patients with higher levels of blood periostin, blood eosinophil counts, or F ENO values. Busse et al 10 confirmed that patients with eosinophil counts of greater than 300 cells/ m L responded better to omalizumab, with up to a 60% decrease in asthma exacerbations. Efficacy studies of other biologics to treat type 2–high asthma have included highly enriched patient populations. Using a similar approach, we examined data from 2 phase III clinical trials of omalizumab in patients with allergic asthma. 11 Differences in rates of asthma exacerbations between the omali- zumab (n 5 542) or placebo (n 5 529) groups during the 16- week inhaled corticosteroid dose-stable phase were evaluated with respect to baseline blood eosinophil counts and baseline markers of asthma severity. The rate of exacerbations requiring 3 or more days of systemic corticosteroid treatment was 0.066 and 0.147 with omalizumab versus placebo, representing a rela- tive rate reduction in omalizumab-treated patients of 55% (95% CI, 32% to 70%; P 5 .002). Mean exacerbation rate reductions associated with omalizumab by baseline blood eosinophil strata were as follows: 200/ m L or greater, 52% (95% CI, 20.3% to 71.5%; P 5 .005); 300/ m L or greater, 65% (95% CI, 30.6% to 82.0%; P 5 .003); and 400/ m L or greater, 72% (95% CI, 34.9% to 87.6%; P 5 .003). In patients with more severe asthma (emer- gency asthma treatment or asthma hospitalization in the prior

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