Omalizumab

Abstract
Omalizumab (Xolair®) is a humanized monoclonal antibody used in the treatment of adolescent and adult patients with moderate to severe allergic asthma inadequately controlled with inhaled corticosteroids (ICS). It selectively binds to circulating immunoglobulin E (IgE) and, thereby, prevents binding of IgE to mast cells and other effector cells. Without surface-bound IgE, these cells are unable to recognize allergens, thus preventing cellular activation by antigens and the subsequent allergic/asthmatic symptoms. Omalizumab decreases free serum IgE levels in a dose-dependent manner, reduces IgE receptor density on effector cells, and significantly improves airway inflammation parameters. Omalizumab is slowly absorbed after subcutaneous administration, and mean elimination half-life is 26 days, thus allowing infrequent administration of the drug. Omalizumab dosage is determined by bodyweight and pretreatment serum total IgE levels. Patients treated with subcutaneous omalizumab in clinical trials received a dosage that was approximately equal to 0.016 mg/kg/IgE (IU/mL) per 4 weeks. Thus, patients received 150 or 300mg every 4 weeks, or 225, 300, or 375mg every 2 weeks. In adults and adolescents (≥12 years of age) with moderate to severe allergic asthma, subcutaneous administration of omalizumab as add-on therapy with ICS improved the number of asthma exacerbations, rescue medication use, asthma symptom scores, and quality-of-life (QOL) scores compared with placebo during 28- and 32-week double-blind trials. In addition, concomitant ICS use was significantly decreased in patients receiving omalizumab, and in the two largest double-blind trials approximately 40% of omalizumab recipients completely withdrew from ICS therapy while maintaining effective asthma control. In general, results of extension studies showed that the beneficial effects of omalizumab were maintained over a total period of 52 weeks. Omalizumab was well tolerated as add-on therapy with ICS during treatment for up to 52 weeks. Common adverse events in clinical trials included injection site reaction, viral infection, upper respiratory tract infection, sinusitis, headache, and pharyngitis, although the incidence of adverse events with omalizumab was similar to that with placebo. Conclusion: Omalizumab, as add-on therapy with ICS, is an effective and well tolerated agent for the treatment of moderate to severe allergic asthma in adolescents and adults. In addition to its symptomatic and QOL benefits, omalizumab therapy allows ICS dosage reduction or discontinuation of ICS in many patients. Comparisons of omalizumab with other asthma therapies have yet to be conducted; however, clinical efficacy and tolerability data indicate that omalizumab is a valuable option in the treatment of allergic asthma. Omalizumab is a humanized recombinant immunoglobulin G (IgG) monoclonal antibody that selectively binds to the Cε3 domain of free IgE at the FcεR1 binding site. This, in turn, prevents IgE binding to mast cells and other effector cells, rendering them unable to detect allergens and, thereby, preventing the cellular activation by antigen and the associated allergic/asthmatic symptoms. In patients with allergic asthma, omalizumab rapidly decreased serum free IgE levels in a dose-dependent manner. In clinical trials of 28 weeks’ duration, subcutaneous treatment with omalizumab resulted in median reductions in serum free IgE levels of 89–99%. After discontinuation of omalizumab therapy, serum free IgE levels slowly increased to the original level over a number of weeks to months. In patients with allergic asthma, omalizumab decreased high-affinity IgE receptor expression by 2 log increments. Furthermore, median basophil FcεR1 density was decreased by ≈97% after 3 months of treatment with omalizumab in a study in patients with allergic rhinitis, with or without allergic asthma. In patients with allergic asthma, treatment with omalizumab, but not placebo, significantly improved various mediators of airway inflammation. Sputum eosinophils were significantly reduced in patients treated with omalizumab when compared to placebo in a double-blind trial. In other studies, treatment with omalizumab decreased antigen-induced histamine release by 65–90% and cellular inflammatory late-asthmatic response by 80%. Statistically significant reductions were also observed in blood eosinophil counts, interleukin-13 levels, and skin-prick test reactivity with omalizumab versus placebo. In well designed trials, treatment with omalizumab significantly attenuated the early- and late-phase asthmatic airway responses to an allergen challenge. Compared with baseline values in one study, the median concentration of allergen required to cause a fall in forced expiratory volume in 1 second (FEV1) of 15% (PC15) was increased by 2.7 doubling doses after 77 days of treatment with omalizumab. Subcutaneous omalizumab is slowly absorbed, with peak serum concentrations observed after an average of 7–8 days. Mean absolute bioavailability of omalizumab is 62% and the drug demonstrates linear pharmacokinetics at doses >0.5 mg/kg. The distribution volume of omalizumab is 78 mL/kg. In patients with allergic asthma, the terminal elimination half-life averaged 26 days, with an apparent clearance of 2.4 mL/kg/day. On the basis of data from animal studies, urinary excretion appears to be the major route of elimination. Subcutaneous omalizumab ≥0.016 mg/kg/IgE (IU/mL) per 4 weeks, as add-on therapy with inhaled corticosteroids (ICS), significantly reduced the mean number of asthma exacerbations per patient and the percentage of patients experiencing an acute exacerbation during 28 or 32 weeks of therapy. In the two largest, double-blind, randomized studies, 14.6% and 12.8% of omalizumab recipients experienced an asthma exacerbation during the 16-week...