World Allergy Forum - IgE: Bench to Bedside
Anti-IgE in Asthma
Thomas B. Casale
IgE plays a central role in allergic reactions of the respiratory tract. In genetically predisposed individuals, IgE molecules specific for allergens are synthesized and released into the circulation by B-cells and plasma cells. The IgE molecule then binds to specific cell surface receptors located on mast cells, basophils, and other immune effector cells. Upon subsequent allergen exposure, allergen molecules bind to the Fab portion of the IgE molecule on the surface of mast cells and basophils, forming cross links and stimulating degranulation of these cells. The degranulation results in the release of mediators and cytokines that ultimately results in the pathophysiologic consequences and symptoms of allergic rhinitis and asthma.
Epidemiologic studies have confirmed the importance of IgE in allergic respiratory disorders. The prevalence of asthma has been shown to be related to the level of serum IgE, and serum IgE levels are also related to persistent wheezing in children. Serum IgE levels have been shown to predict human airway reactivity in vitro. Thus, both epidemiologic and basic research studies have confirmed a clear relationship between IgE and the pathogenesis and development of symptoms associated with allergic respiratory diseases.
Because of the central role that IgE plays in allergic respiratory reactions, therapy to inhibit IgE mediated responses through the use of anti-IgE antibodies is a logical step. rhuMAb-E25, omalizumab, is a recombinant humanized monoclonal anti-IgE antibody that binds to IgE on the same FC site as FCåR1. This binding decreases free serum IgE by forming biologically inactive immune complexes with free IgE. Since omalizumab does not bind to IgE on mast cells and basophils, it is not anaphylactogenic.
Decreasing total serum IgE in atopic patients should decrease the available amounts of antigen-specific IgE to bind to and sensitize tissue mast cells and basophils. This reduction of available IgE should therefore lead to a decrease in IgE-mediated symptoms and improve control of atopic diseases. In allergic rhinitis studies, omalizumab induced reductions in serum-free IgE levels were correlated with symptom improvement.
To test the therapeutic potential of omalizumab for the therapy of asthma, several proof of concept studies were done. Omalizumab was found to inhibit both the early and late asthmatic response due to allergen as well as the subsequent development of airway hyperresponsiveness and sputum eosinophilia. Omalizumab was also shown to inhibit allergen-induced skin test responses. Finally, omalizumab decreased the number of IgE receptors found on basophils concomitant with a reduction of serum IgE levels.
Clinical protocols designed to study the efficacy of omalizumab in asthma have shown its capacity to be an effective and safe therapy for this disorder. In three pivotal trials, the efficacy and safety of omalizumab versus placebo was examined in symptomatic adults and adolescents treated with inhaled corticosteroids and asymptomatic children treated with corticosteroids.
The primary outcome measures were the number of asthma exacerbations per patient in the adults and adolescents and the inhaled corticosteroid requirement in children. Secondary outcome measures included number of patients with asthma exacerbations, inhaled corticosteroid requirement, safety and tolerability, quality of life, symptoms, rescue medication use and lung function. The study designs involved a 4 - 6 week run-in phase where the dose of inhaled corticosteroid was optimized. Subsequently, patients were treated with either omalizumab or placebo plus the stable dose of beclomethasone for 16 weeks. This was followed by a 12 week steroid withdrawal phase. Finally, a double-blind extension phase of 20 weeks was included.
In the adult studies, the mean starting dose of beclomethasone was about 650 to 750 mcg/day and the mean dose in the pediatric study was approximately 330 mcg/day. Omalizumab was found to reduce the frequency of exacerbations during the add-on phase as well as the steroid withdrawal phase. In addition, omalizumab demonstrated greater inhaled corticosteroid dose reduction capacity than did placebo. A greater number of omalizumab patients withdrew completely from inhaled corticosteroids versus the placebo group in all three studies.
In the adult study, there was significant decrease in nocturnal asthma symptoms, beta agonist puffs per day and nighttime symptom scores, and FEV1 % predicted increased. Omalizumab also decreased the number of asthma-related medical visits, emergency room visits, and hospitalizations. Finally, omalizumab was shown to improve quality of life in comparison to the placebo. The adverse event profile was similar in the anti-IgE (omalizumab) and placebo treated groups. Adverse events were generally regarded as mild or moderate in intensity. No reported anaphylactic reactions or serum sickness was found in the omalizumab treated patients.
Thus, in adults, adolescents and children with moderate to severe atopic asthma, omalizumab prevented asthma exacerbations while allowing reduction or withdrawal of inhaled corticosteroids. Omalizumab-treated patients had an improvement in asthma symptoms despite a significant reduction in rescue medication use. Omalizumab was well tolerated and not reported to have any significant side effects in the patients treated.
In another study involving severe allergic asthmatics, the efficacy and safety of omalizumab was tested. Similarly to the previous results, omalizumab allowed a significant reduction of high dose corticosteroids in previously steroid -dependent severe asthmatics without concomitant worsening of asthma exacerbation symptoms or morning peak expiratory flow. Omalizumab significantly improved quality of life, rescue inhaler use, and asthma symptom scores despite the steroid reduction. The omalizumab-treated patients did not have significant side effects.
Thus, omalizumab has been shown to improve asthma. Omalizumab was well tolerated in 1,300 patients treated in asthma studies and SAR trials. Omalizumab reduced asthma exacerbations and hospitalizations and allowed reduction or withdrawal of inhaled corticosteroids. Coupled with its effects in allergic rhinitis, this agent promises to be a novel and promising therapeutic agent to add to our armamentarium for the treatment of allergic respiratory disorders.
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