Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab)

Background and Objective. There seems to be a strong causal relationship be tween allergy and the origins of asthma. Susceptibility to both is determin ed by a combination of genetics and environment acting through a complex ne twork of cytokines. Nearly 90% of affected children have positive skin test s indicating the presence of specific immunoglobulin E (IgE), with sensitiv ity to house dust mite, Alternaria, cockroach, cat, and dog most closely li nked to the disease. Greater exposure to house dust mite during infancy lea ds to earlier onset of wheezing, and elevated serum IgE levels correlate wi th the appearance of asthma symptoms. Specific IgE binds to high-affinity ( Fc epsilon RI) receptors on mast cells and basophils. The IgE-mediated reac tions that follow exposure of sensitized mast cells to an allergen are desi gnated early- and late-phase asthmatic responses (EAR and LAR). EAR is char acterized by release of histamine and other preformed mediators within 1 ho ur of allergen exposure. It is often followed by LAR, an infiltration of th e airways by inflammatory cells associated with an episode of more prolonge d, and usually more severe airflow obstruction, 4 to 8 hours after antigen exposure. Chronic airway symptoms result from persistent LAR caused by cont inuous allergen exposure. IgE antibodies are capable of passive transfer of both EAR and LAR sensitivity. IgE-mediated mast cell activation contribute s to chronic tissue eosinophilia and airway remodeling, with permanent loss in pulmonary function. Omalizumab (rhuMAb-E25) is a recombinant, humanized, monoclonal anti-IgE an tibody of mouse origin developed for the treatment of IgE-mediated diseases . Omalizumab binds to free IgE at the same site as the high-affinity recept or. Although it attaches to free IgE, it does not bind to IgA, IgG, or cell -bound IgE. It therefore does not induce cross-linking of cell-bound IgE, w hich would lead to the release of allergic mediators. It has been reported to decrease serum IgE levels in a dose-dependent manner, inhibit EAR and LA R, and cause a down-regulation of Fc epsilon RI receptors on basophils. Oma lizumab has been reported to be safe and effective in improving asthma cont rol and reducing the requirement for oral and inhaled corticosteroids. This double-blind, randomized, placebo-controlled study evaluated the safety, s teroid-sparing effects, and impact on disease exacerbations of omalizumab i n the treatment of childhood asthma. Methods. Participants were 334 males and premenarchal females aged 6 to 12 years, with moderate to severe allergic asthma requiring treatment with inh aled corticosteroids. During a run-in phase, all children were switched to equivalent doses of beclomethasone dipropionate (BDP), and the dose was adj usted to assure maintenance of asthma control achieved with previous cortic osteroid treatment. Children were randomized to subcutaneously administered placebo (N = 109) or omalizumab (N = 225) at a dose based on body weight a nd initial serum IgE (0.016 mg/kg/IgE [IU/mL] per 4 weeks). BDP dose (initi al range 168-420 mug/d) was kept stable for 16 weeks (stable-steroid phase) , reduced over 8 weeks to the minimum effective dose (steroid-reduction pha se), and maintained constant for the final 4 weeks. Results. More participants in the omalizumab group decreased their BDP dose , and their reduction was greater than that of the placebo group (median re duction 100% vs 66.7%). BDP was withdrawn completely in 55% of the omalizum ab group versus 39% of the placebo group. The incidence and the frequency of asthma exacerbations requiring treatment with doubling of BDP dose or systemic corticosteroids were lower in the om alizumab group. The treatment differences were statistically significant du ring the steroid-reduction phase, during which fewer participants in the om alizumab group had asthma exacerbation episodes (18.2% vs 38.5%), and the m ean number of episodes per patient was smaller than with placebo (0.42 vs 2 .72). Five asthma exacerbations requiring hospitalization all occurred in t he placebo group. Participants' and investigators' global evaluations of treatment effectiven ess were more favorable for omalizumab than placebo. Investigators rated ef fectiveness excellent for 31.5% of the omalizumab group versus 16.3% of the placebo group and good for 44.7% of the omalizumab group versus 32.7% of t he placebo group. There was little change in asthma symptom scores or spirometry measurements during either the stable-steroid or steroid dose-reduction phase, with min imal differences between the treatment groups. The requirement for rescue medication in the omalizumab group during both t he stable-steroid and steroid dose-reduction phases was consistently lower than at baseline. At week 28, the median number of puffs of rescue medicati on taken daily was 0 in the omalizumab group and 0.46 in the placebo group. The change from baseline was significant in favor of omalizumab. Over the entire treatment period, patients in the omalizumab group missed a mean of 0.65 school days, compared with a mean of 1.21 days in the placebo group. The mean number of unscheduled medical contacts attributable to ast hma-related medical problems was significantly smaller in the omalizumab gr oup than in the placebo group throughout the treatment period (0.15 vs 5.35 ). Median reduction in serum free IgE was 95% to 99% among omalizumab patients . Median free IgE ranged from 133 to 790 IU/mL at baseline and was in the r ange of 6 to 9 IU/mL during the treatment period. The dosing scheme used in the trial therefore effectively reduced serum IgE in patients with initial concentrations as high as 1300 IU/mL. There was no reduction in free IgE i n the placebo group. Omalizumab treatment was well tolerated. There were no serious treatment-re lated adverse events. The frequency and types of all adverse events were si milar in the omalizumab and placebo groups. The majority of adverse events were mild to moderate in severity. No adverse events suggestive of serum si ckness or immune complex formation were observed. Study-drug-related advers e events occurred more frequently in the omalizumab group than in the place bo group (6.2% vs 0.9%). Urticaria was reported in 9 omalizumab patients (4 %) compared with 1 (0.9%) placebo patient and was mild or moderate in nearl y all cases. Conclusion. Treatment with omalizumab is safe in children with asthma. It r educes the requirement for inhaled corticosteroids while protecting against disease exacerbation.